SI9300346A - Morpholine and thiomorpholine tachyquinine-receptor antagonists - Google Patents

Morpholine and thiomorpholine tachyquinine-receptor antagonists Download PDF

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SI9300346A
SI9300346A SI9300346A SI9300346A SI9300346A SI 9300346 A SI9300346 A SI 9300346A SI 9300346 A SI9300346 A SI 9300346A SI 9300346 A SI9300346 A SI 9300346A SI 9300346 A SI9300346 A SI 9300346A
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trifluoromethyl
phenyl
bis
benzyloxy
mmol
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SI9300346A
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Conrad P Dorn
Jeffrey J Hale
Malcolm Macoos
Sander G Mills
Tamara Ladduwahetty
Shrenik K Shah
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Merck & Co Inc
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    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
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    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

Substituted heterocycles of the general structural formula: <CHEM> are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, and asthma and calcium channel blockers useful in the treatment of cardiovascular conditions such as angina, hypertension or ischemia.

Description

(57) Substituirani heterocikli s splošno strukturno formulo:(57) Substituted heterocycles of general structural formula:

Sl 9300346 ASl 9300346 A

so tahikinin receptorski antagonisti uporabni pri zdravljenju vnentnih bolezni, bolečine ali migrene in astme, in so blokerji kalcijevega kanala uporabni pri zdravljenju kardiovaskularnih stanj, kot je angina, hipertenzija ali ishemija.tachykinin receptor antagonists are useful in the treatment of disease, pain or migraine and asthma, and calcium channel blockers are useful in the treatment of cardiovascular conditions such as angina, hypertension or ischemia.

MERCK & CO., INC.MERCK & CO., INC.

Morfolin in tiomorfolin tahinin receptorski antagonistiMorpholine and thiomorpholine tachinin receptor antagonists

Povzetek izumaSummary of the Invention

Predložena prijava je delna nadaljevalna prijava prijave, ki je istočasno v postopku, serijska št. 07/971,448, vložene 04. novembra 1992, ki je delna nadaljevalna prijava prijave, kije istočasno v postopku, serijska št. 07/905,976, vložene 29. junija 1992.The application submitted is a partial continuation application, which is pending at the same time, serial no. No. 07 / 971,448, filed November 04, 1992, which is a partial continuation of the application at the same time as the proceedings, serial no. No. 07 / 905,976, filed June 29, 1992.

Predloženi izum se nanaša na nove spojine, ki so predstavljene s strukturno formulo I:The present invention relates to novel compounds represented by structural formula I:

kjer so ti R1, R2, R3, R4, R5 in X definirani v nadaljevanju.wherein these R 1 , R 2 , R 3 , R 4 , R 5 and X are defined below.

Izum se tudi nanaša na farmacevtske pripravke, ki vključujejo te nove spojine kot aktivne sestavine in na uporabo novih spojin in njihovih pripravkov pri zdravljenju določenih motenj.The invention also relates to pharmaceutical preparations incorporating these novel compounds as active ingredients and to the use of novel compounds and their preparations in the treatment of certain disorders.

Spojine predloženega izuma so tahikinin receptorski antagonisti in so uporabne pri zdravljenju vnetnih bolezni, bolečine ali migrene in astme.The compounds of the present invention are tachykinin receptor antagonists and are useful in the treatment of inflammatory diseases, pain or migraines and asthma.

Nekatere od teh spojin so tudi blokerji kalcijevega kanala in so uporabne pri zdravljenju kardiovaskularnih motenj, kot je angina, hipertenzija ali ishemija.Some of these compounds are also calcium channel blockers and are useful in the treatment of cardiovascular disorders such as angina, hypertension or ischemia.

Ozadje izumaBACKGROUND OF THE INVENTION

Analgezijo so zgodovinsko dosegali v centralnem živčnem sistemu z opiati in analogi, ki se jih navadimo, in periferno z inhibitorji ciklooksigenaze, ki imajo želodčne stranske učinke. Snov P antagonisti lahko sprožijo analgezijo tako centralno kot periferno. Poleg tega so snov P antagonisti inhibitorji nevrogenega vnetja.Analgesia has historically been achieved in the central nervous system by opiates and habitual analogues and peripherally by cyclooxygenase inhibitors, which have gastric side effects. Substance P antagonists can trigger analgesia both centrally and peripherally. In addition, substance P antagonists are inhibitors of neurogenic inflammation.

Nevropeptidni receptorji za snov P (nevrokinin-1; NK-1) so široko razporejeni po vsem živčnem sistemu sesalcev (posebno možganih in hrbteničnih ganglijih), cirkularnem sistemu in perifernih tkivih (še posebno dvanajstniku in zgornjem tankem črevesju) in so vključeni v regulacijo številnih izmed raznovrstnih bioloških procesov. To vključuje senzorično percepcijo vonja, vida, sluha in bolečine, kontrolo gibanja, želodčno motiliteto, vazodilatacijo, izločanje sline in mokrenje (B. Pernow, Pharmacol, Rev., 1983, 35, 85-141). NK1 in NK2 receptorska podtipa sta vključena v sinaptični prenos (Laneuville et al., Life Sci., 42:1295-1305 (1988)).Neuropeptide receptors for substance P (neurokinin-1; NK-1) are widely distributed throughout the mammalian nervous system (especially the brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and upper small intestine) and are involved in the regulation of many among the diverse biological processes. This includes sensory perception of odor, vision, hearing and pain, movement control, gastric motility, vasodilation, salivation and urination (B. Pernow, Pharmacol, Rev., 1983, 35, 85-141). NK1 and NK2 receptor subtypes are involved in synaptic transmission (Laneuville et al., Life Sci., 42: 1295-1305 (1988)).

Receptor za snov P je član naddružine G proteinsko-spojenih receptorjev. Ta naddružina je izredno raznolika skupina receptorjev v pogojih aktiviranja ligandov in bioloških funkcij. Poleg tahikininskih receptorjev, ta receptorska naddružina vključuje opsine, adrenergične receptorje, muskarinske receptorje, dopaminske receptorje, serotoninske receptorje, tiroid-stimulirajočega hormonskega receptorja, receptor luteinizirnega hormona-koriogonadotropnega hormona, produkt rakotvorne ras, receptorje faktorja parjenja kvasovk Dictyostelium cAMP receptor in receptorje za ostale hormone in nevrotransmiterje (glej A.D. Hershey, et al., J. Biol. Chem., 1991, 226, 4366-4373).The substance P receptor is a member of the G family of protein-coupled receptors. This superfamily is an extremely diverse group of receptors under conditions of ligand activation and biological functions. In addition to tachykinin receptors, this receptor subfamily includes opsins, adrenergic receptors, muscarinic receptors, dopamine receptors, serotonin receptors, thyroid-stimulating hormone receptors, luteinising hormone-choriogonadotropic hormone receptors, carcinogenic product, yeast mating receptors and receptors hormones and neurotransmitters (see AD Hershey, et al., J. Biol. Chem. 1991, 226, 4366-4373).

Snov P (tu notri imenovana tudi SP) je nativni undekapeptid, ki sodi v tahikininsko družino peptidov, pri čemer so zadnji t.i. zaradi njihovega takojšnjega kontraktilnega delovanja na ekstravaskularno tkivo gladkega mišičja. Za tahikinine je značilno ohranjene karboksilne terminalne sekvence Phe-X-Gly-Leu-Met-NH2. Poleg SP znani sesalski tahikinini vključujejo nevrokinin A in nevrokinin B. Sodobna nomenklatura imenuje receptorje za SP, nevrokinin A in nevrokinin B kot NK-1, NK-2 oz. NK-3.Substance P (also referred to here as SP) is a native undecapeptide belonging to the tachykinin family of peptides, the latter being due to their immediate contractile action on extravascular smooth muscle tissue. Tachykinins are characterized by conserved carboxylic terminal sequences of Phe-X-Gly-Leu-Met-NH 2 . In addition to SP, known mammalian tachykinins include neurokinin A and neurokinin B. Modern nomenclature names the receptors for SP, neurokinin A, and neurokinin B as NK-1, NK-2, or. NK-3.

Bolj določeno, je snov P farmakološko-aktiven nevropeptid, ki ga proizvajajo sesalci in ima značilno amino kislinsko sekvenco, kije ponazorjena spodaj:More specifically, substance P is a pharmacologically active neuropeptide produced by mammals and having a characteristic amino acid sequence illustrated below:

Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (Chang et al., Nature New Biol. 232, 86 (1971); D.F. Veber et al., ZDA patent št. 4,680,283).Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH 2 (Chang et al., Nature New Biol. 232, 86 (1971); DF Veber et al., U.S. Pat. 4,680,283).

Nevrokin A ima naslednjo amino kislinsko sekvenco:Neurokin A has the following amino acid sequence:

His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2.His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH 2 .

Nevrokinin B ima naslednjo amino kislinsko sekvenco:Neurokinin B has the following amino acid sequence:

Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2.Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH 2 .

Snov P deluje kot vazodilator, depresant, stimulira slinjenje in proizvaja povečano kapilarno permeabilnost. Sposobna je tudi povzročanja tako analgezije kot hiperalgezije pri živalih, odvisno od doze in bolečinske odzivnosti živali (glej R.C.A. Frederickson et al., Science, 199, 1359 (1978); P. Oehme et al., Science, 208, 305 (1980)) in igra vlogo pri senzoričnem prenosu in bolečinski percepciji (T.M. Jessell, Advan. Biochem. Psychopharmacol. 28, 189 (1981)). Na primer, verjamejo, da je snov P med drugim vključena v nevrotransmisijo občutkov bolečine [Otsuka et al, Role of Substance P as a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia v 1982 Substance P in the Nervous System, Ciba Foundation Syposium 91, 13-34 (objavil Pitman) in Otsuka in Yanagisawa, Does Substance P Act as a Pain Transmitter? TIPS (dec. 1987) 8 506-510. Še posebno je bilo prikazano, daje snov P vključena v transmisijo bolečine pri migreni (glej B.E.B. Sandberg et al., Journal of Medicinal Chemistry, 25, 1009 (1982)), in pri artritisu (Levine et al. Science, (1984) 226 547-549). Ti peptidi so tudi vključeni v gastrointestinalne (Gl) motnje in bolezni Gl trakta, kot je vnetna črevesna bolezen, ulcerativni kolitis in Crohnova bolezen, itd. (glej Mantyh et al., Neuroscience, 25 (3), 817-37 (1988) in D. Regoli v Trends in Cluster Headache Ed. F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, 1987, str. 85-95).Substance P acts as a vasodilator, depressant, stimulates salivation and produces increased capillary permeability. It is also capable of causing both analgesia and hyperalgesia in animals, depending on the dose and pain response of the animal (see RCA Frederickson et al., Science, 199, 1359 (1978); P. Oehme et al., Science, 208, 305 (1980). ) and plays a role in sensory transmission and pain perception (TM Jessell, Advan. Biochem. Psychopharmacol. 28, 189 (1981)). For example, substance P is believed to be involved, among other things, in the neurotransmission of pain sensations [Otsuka et al, Role of Substance P as a Sensory Transmitter and Spinal Cord and Sympathetic Ganglia in 1982 Substance P in the Nervous System, Ciba Foundation Syposium 91, 13 -34 (Posted by Pitman) and Otsuka and Yanagisawa, Does Substance P Act as a Pain Transmitter? TIPS (Dec 1987) 8 506-510. In particular, substance P has been shown to be involved in the transmission of migraine pain (see BEB Sandberg et al., Journal of Medicinal Chemistry, 25, 1009 (1982)), and in arthritis (Levine et al. Science, (1984) 226 547-549). These peptides are also involved in gastrointestinal (Gl) disorders and Gl tract disorders such as inflammatory bowel disease, ulcerative colitis and Crohn's disease, etc. (see Mantyh et al., Neuroscience, 25 (3), 817-37 (1988) and D. Regoli in Trends and Cluster Headache by Ed. F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, 1987, pp. 85- 95).

Domnevajo tudi, da obstaja nevrogenski mehanizem za artritis, v katerem lahko snov P igra vlogo (Kidd et al., A Neurogenic Mechanism for Symmetric Arthritis v The Lancet, 11 November 1989 in Gronblad et al., Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis v J. Rheumatol. (1988) 15(12) 1807-10). Potemtakem smatrajo, da je snov P vključena v vnetni odziv pri boleznih, kot je revmatoidni artritis in osteoartritis (O’Byrne et al., v Arthritis and Rheumatism (1990) 33 1023-8). Ostala bolezenska področja, kjer smatrajo, da so tahikininski antagonisti uporabni, so alergijsko stanje (Hamelet et al., Can. J. Pharmacol. Physiol. (1988) 66 1361-7), imunoregulacija (Lotz et al., Science (1988) 241 1218-21, Kimball et al., J. Immunol. (1988) 141 (10) 3564-9 in A. Perianin, et al.,It has also been suggested that there is a neurogenic mechanism for arthritis in which substance P may play a role (Kidd et al., A Neurogenic Mechanism for Symmetric Arthritis in The Lancet, 11 November 1989 and Gronblad et al., Neuropeptides and Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis in J. Rheumatol. (1988) 15 (12) 1807-10). Therefore, substance P is thought to be involved in an inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis (O'Byrne et al., In Arthritis and Rheumatism (1990) 33 1023-8). Other disease areas where tachykinin antagonists are considered useful are allergic conditions (Hamelet et al., Can. J. Pharmacol. Physiol. (1988) 66 1361-7), immunoregulation (Lotz et al., Science (1988) 241 1218-21, Kimball et al., J. Immunol. (1988) 141 (10) 3564-9, and A. Perianin, et al.,

Biochem. Biophys. Res. Commun. 161, 520 (1989)) vasodilacija, bronhospazem, refleksna ali nevronska kontrola droba (Mantyh et al., PNAS (1988) 85 3235-9) in morda z ustavitvijo ali upočasnitvijo β-amiloid-posredovanih nevrodegenerativnih sprememb (Yankner et al., Science, (1990) 250, 279-82) pri senilni demenci alzheimerjeva tipa, Alzheimerjevi bolezni in Down-ovem sindromu. Snov P lahko tudi opravlja funkcijo pri demielinacijskih boleznih, kot je multipla skleroza in amiotropna lateralna skleroza [J. Luber-Narod et. al., oris naj bi bil prikazan na C.I.N.P. XVIII. kongresu, 28. junij - 2. julij 1992, v tisku]. Antagonisti, selektivni za nevrokinin-1 (NK-1) in/ali nevrokinin-2 (NK-2) receptor so lahko uporabni pri zdravljenju astmatične bolezni (Frossard et al., Life Sci., 49, 1941-1953 (1991); Advenier, et al., Biochem. Biophys. Res. Comm., 184(3), 1418-1424 (1992)).Biochem. Biophys. Really. Commun. 161, 520 (1989)) vasodilation, bronchospasm, reflex or neuronal control of the drug (Mantyh et al., PNAS (1988) 85 3235-9) and possibly by arresting or slowing β-amyloid-mediated neurodegenerative changes (Yankner et al. Science, (1990) 250, 279-82) in senile dementia of Alzheimer's type, Alzheimer's disease and Down syndrome. Substance P may also function in demyelinating diseases such as multiple sclerosis and amyotropic lateral sclerosis [J. Luber-People et. al., the outline is to be shown on the C.I.N.P. XVIII. to Congress, June 28-July 2, 1992, in press]. Antagonists selective for neurokinin-1 (NK-1) and / or neurokinin-2 (NK-2) receptor may be useful in the treatment of asthmatic disease (Frossard et al., Life Sci., 49, 1941-1953 (1991); Advenier, et al., Biochem. Biophys. Res. Comm., 184 (3), 1418-1424 (1992).

Snov P antagonisti so lahko uporabni pri posredovanju nevrogenskega izločanja sluzi v zračnih poteh sesalcev in od tod zagotovijo zdravljenje in simptomatično olajšanje pri boleznih, za katere je značilno izločanje sluzi, še posebno cistični fibrozi [S. Ramnarine, et al., povzetek naj bi bil predstavljen na 1993 ALA/ATS Int’l konferenci, 1619 maj 1993, naj bi bilo objavljeno v Am. Rev. of Respiratoy Dis., May 1993, v tisku].Substance P antagonists can be useful in mediating the neurogenic secretion of mucus in mammalian airways and hence provide treatment and symptomatic relief in diseases characterized by mucus secretion, especially cystic fibrosis [S. Ramnarine, et al., Abstract to be presented at the 1993 ALA / ATS Int'l Conference, May 1619, 1993, to be published in Am. Rev. of Respiratoy Dis., May 1993, in press].

V nedavni preteklosti so naredili nekaj poizkusov, da bi zagotovili peptidom podobne snovi, ki so antagonisti za snov P in ostale tahikininske peptide, da bi bolj učinkovito zdravili različne motnje in bolezni, ki so navedene zgoraj. Za primer glej evropske patentne prijave (EPO objava št. 0,347,802, 0,401,177 in 0,412,452), ki opisujejo različne peptide kot nevrokinin A antagoniste. Podobno EPO objava št. 0,336,230 opisuje heptapeptide, ki so snov P antagonisti uporabni pri zdravljenju astme. Merckov U.S patent št. 4,680,283 tudi opisuje peptidne analoge snovi P.In the recent past, some attempts have been made to provide peptide-like substances that are antagonists to substance P and other tachykinin peptides in order to more effectively treat the various disorders and diseases mentioned above. For an example, see European Patent Applications (EPO Publication Nos. 0,347,802, 0,401,177, and 0,412,452), which describe various peptides as neurokinin A antagonists. Similarly, EPO Publication no. No. 0,336,230 describes heptapeptides, which are substance P antagonists useful in the treatment of asthma. Merck's U.S patent no. No. 4,680,283 also describes peptide analogues of substance P.

Določeni inhibitorji tahikininov so opisani v U.S. patentu št. 4,501,733, z nadomestitvijo ostankov v sekvenci snovi P s Trp ostanki.Certain tachykinin inhibitors are described in U.S. Pat. patent no. No. 4,501,733, by replacing the residues in the sequence of substance P with Trp residues.

Nadaljnji razred tahikininskih receptorskih antagonistov, ki vključuje monomerno ali dimerno heksa- ali heptapeptidno enoto v linearni ali ciklični obliki, je opisan v GBA-2216529.A further class of tachykinin receptor antagonists comprising a monomer or dimeric hexa- or heptapeptide unit in linear or cyclic form is described in GBA-2216529.

Peptidu podobna narava takšnih snovi jih naredi z metabolnega stališča preveč labilne, da bi lahko služili kot praktična terapevtska sredstva pri zdravljenju bolezni. Ne-peptidni antagonisti v smislu predloženega izuma pa, po drugi strani, nimajo te slabe strani, ker pričakujemo, da so z metabolnega stališča bolj stabilni kot prej opisana sredstva.The peptide-like nature of such substances makes them, from a metabolic point of view, too labile to serve as practical therapeutic agents in the treatment of disease. Non-peptide antagonists of the present invention, on the other hand, do not have this disadvantage, because they are expected to be more stable from the metabolic point of view than the agents described previously.

V stroki je znano, da baclofen (/3-(aminoetil)-4-klorobenzenpropanojska kislina) v centralnem živčnem sistemu učinkovito blokira vzdražljivostno delovanje snovi P, toda ker so v številnih področjih vzdražljivostni odzivi na druge spojine, kot je acetilholin in glutamat prav tako inhibirani, baclofena ne smatramo za specifičnega antagonista snovi P. Pfizer-jeve WIPO patentne prijave (PCT objava št. WO 90/05525, WO 90/05729, WO 91/18899, WO 92/12151 in WO 92/12152) in objave (Science, 251, 435-437 (1991); Science, 251, 437-439 (1991); J. Med. Chem., 35, 2591-2600 (1992)) opisujejo 2-arilmetil-3-substituirane amino-kvinuklidinske derivate, za katere je opisano, da so uporabni kot snov P antagonisti za zdravljenje gastrointestinalnih motenj, motenj centralnega živčnega sistema, vnetnih bolezni in bolečine ali migrene. Glaxo evropska patentna prijava (EPO objava št. 0,360,390) opisuje različne spirolaktam-substituirane amino kisline in peptide, ki so antagonisti ali agonisti snovi P. Pfizer-jeva WIPO patentna prijava (PCT objava št. WO 92/06079) opisuje kondenzirano-obročne analoge nearomatskih hterociklov, ki vsebujejo dušik, kot uporabne za zdravljeje bolezni posredovanih s prebitkom snovi P. Pfizer-jeva WIPO patentna prijava (PCT objava št. WO 92/15585 opisuje l-azabiciklo[3.2.2]nonan-3-aminske derivate kot snov P antagoniste. Sanofi-jeva objava (Life Sci., 50, PL101-PL106 (1992) opisuje 4-fenil piperidinski derivat kot antagonist nevrokinin A (NK2) receptorja.It is well known in the art that baclofen (/ 3- (aminoethyl) -4-chlorobenzenepropanoic acid) effectively blocks the excitatory action of substance P in the central nervous system, but in many areas, the irritant responses to other compounds such as acetylcholine and glutamate are also inhibited, baclofen is not considered to be a specific substance antagonist of P. Pfizer's WIPO patent application (PCT Publication No. WO 90/05525, WO 90/05729, WO 91/18899, WO 92/12151 and WO 92/12152) and Publications ( Science, 251, 435-437 (1991); Science, 251, 437-439 (1991); J. Med. Chem., 35, 2591-2600 (1992)) describe 2-arylmethyl-3-substituted amino-quinuclidine derivatives , which have been described as useful as substance P antagonists for the treatment of gastrointestinal disorders, central nervous system disorders, inflammatory diseases, and pain or migraine. Glaxo European Patent Application (EPO Publication No. 0,360,390) describes various pyrrolactam-substituted amino acids and peptides that are antagonists or agonists of the substance P. Pfizer's WIPO patent application (PCT Publication No. WO 92/06079) describes condensed-ring analogs non-aromatic nitrogen-containing heterocycles as useful for treating surplus-mediated diseases P. Pfizer's WIPO patent application (PCT Publication No. WO 92/15585 describes l-azabicyclo [3.2.2] nonan-3-amine derivatives as a substance P antagonists The Sanofi publication (Life Sci., 50, PL101-PL106 (1992)) describes a 4-phenyl piperidine derivative as a neurokinin A (NK2) receptor antagonist.

Howson et al., (Biorg. & Med. Chem. Lett., 2 (6), 559-564 (1992)) opisuje določene 3-amino in 3-oksi kvinuklidinske spojine in njihovo vezavo na snov P receptorje. EPO objava 0,499,313 opisuje določene 3-oksi in 3-tio azabiciklične spojine kot tahikininske antagoniste. U.S. patent št. 3,506,673 opisuje določene 3-hidroksi kvinuklidinske spojine kot stimulanse centralnega živčnega sistema. Pfizerjeva EPO patentna prijava (EPO objava 0,436,334) opisuje določene 3-aminopiperidinske spojine kot snov P antagoniste. U.S. patent št. 5,064,838 opisuje določene 1,4disubstituirane piperidinilne spojine kot analgetike. PCT objava št. WO 92/12128 opisuje določene piperidinske in pirolidinske spojine kot analgetike. Peyronel, et al. (Biorg & Med. Chem. Lett., 2 (1), 37-40 (1992)) opisuje kondenzirano obročno pirolidinsko spojino kot snov P antagonist. EPO objava št. 0.360,390 opisuje določene spirolaktamske derivate kot snov P antagoniste. U.S. patent št. 4,804,661 opisuje določene piperazinske spoljine kot analgetike. U.S. patent št. 4,943,578 opisuje določene piperazinske spojine, uporabne pri zdravljenju bolečine. PCT objava št. WO 92/01679 opisuje določene 1,4-disubstituirane piperazine, uporabne pri zdravljenju mentalnih motenj, pri katerih je vključen dopaminergični deficit.Howson et al., (Biorg. & Med. Chem. Lett., 2 (6), 559-564 (1992)) describes certain 3-amino and 3-oxy quinuclidine compounds and their binding to substance P receptors. EPO Publication 0,499,313 describes certain 3-oxy and 3-thio azabicyclic compounds as tachykinin antagonists. U.S. patent no. No. 3,506,673 describes certain 3-hydroxy quinuclidine compounds as central nervous system stimulants. Pfizer's EPO patent application (EPO Publication 0,436,334) describes certain 3-aminopiperidine compounds as a substance of the P antagonist. U.S. patent no. No. 5,064,838 describes certain 1,4-disubstituted piperidinyl compounds as analgesics. PCT Publication No. WO 92/12128 describes certain piperidine and pyrrolidine compounds as analgesics. Peyronel, et al. (Biorg & Med. Chem. Lett., 2 (1), 37-40 (1992)) describes a fused ring pyrrolidine compound as a substance P antagonist. EPO Release no. 0.360,390 describes certain spirolactam derivatives as a substance of the P antagonist. U.S. patent no. No. 4,804,661 describes certain piperazine exteriors as analgesics. U.S. patent no. No. 4,943,578 describes certain piperazine compounds useful in the treatment of pain. PCT Publication No. WO 92/01679 describes certain 1,4-disubstituted piperazines useful in the treatment of mental disorders involving dopaminergic deficits.

Natančen opis izumaDetailed description of the invention

Nove spojine predloženega izuma predstavimo s strukturno formulo I:The novel compounds of the present invention are represented by structural formula I:

ali njeno farmacevtsko sprejemljivo soljo, kjer je:or a pharmaceutically acceptable salt thereof, wherein:

R1 izbran iz skupine, ki sestoji iz:R 1 selected from the group consisting of:

(1) vodika;(1) hydrogen;

(2) 6 alkila, nesubstituiranega ali substituiranega z enim ali večimi izmed substituentov izbranih iz:(2) 6 alkyl, unsubstituted or substituted by one or more of the substituents selected from:

(a) hidroksi, (b) okso, (c) alkoksi, (d) fenil-Cj 3 alkoksi, (e) fenila, (f) -CN, (g) halo, (h) -NR9R10, kjer sta R9 in R10 neovisno izbrana iz:(a) hydroxy, (b) oxo, (c) alkoxy, (d) phenyl-C 3 alkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR 9 R 10, wherein R 9 and R 10 are independently selected from:

(i) vodika, (ii) C^ alkila, (iii) hidroksi-C^ alkila in (iv) fenila, (i) -NR9COR10, kjer sta R9 in R10 kot je definirano zgoraj, (j) -NR9CO2R10, kjer sta R9 in R10 kot je definirano zgoraj, (k) -CONR9R10, kjer sta R9 in R10 kot je definirano zgoraj, (l) -COR9, kjer je R9, kot je definirano zgoraj, (m) -COoR9, kjer je R9, kot je definirano zgoraj;(i) hydrogen, (ii) C 1-6 alkyl, (iii) hydroxy-C 1-6 alkyl, and (iv) phenyl, (i) -NR 9 COR 10 , wherein R 9 and R 10 are as defined above, (j) -NR 9 CO 2 R 10 where R 9 and R 10 are as defined above, (k) -CONR 9 R 10 where R 9 and R 10 are as defined above, (l) -COR 9 where R 9 as defined above, (m) -CO o R 9 , wherein R 9 is as defined above;

(n) heterocikla, kjer je heterocikel izbran iz skupine, ki sestoji iz:(n) heterocycle, wherein the heterocycle is selected from the group consisting of:

(A) benzimidazolila, (B) benzofuranila, (C) benzotiofenila, (D) benzoksazolila, (E) furanila, (F) imidazolila, (G) indolila, (H) izooksazolila, (I) izotiazolila, (J) oksadiazolila, (K) oksazolila, (L) pirazinila, (M) pirazolila, (N) piridila, (O) pirimidila, (P) pirolila, (Q) kinolila, (R) tetrazolila, (S) tiadiazolila, (T) tiazolila, (U) tienila, (V) triazolila, (W) azetidinila, (X) 1,4-dioksanila, (Y) heksahidroazepinila, (Z) oksanila, (AA) piperazinila, (AB) piperidinila, (AC) pirolidinila, (AD) tetrahidrofuranila in (AE) tetrahidrotienila, in kjer je heterocikel nesubstituiran ali substituiran z enim ali večimi substituenti, izbranimi iz:(A) benzimidazolyl, (B) benzofuranyl, (C) benzothiophenyl, (D) benzoxazolyl, (E) furanyl, (F) imidazolyl, (G) indolyl, (H) isooxazolyl, (I) isothiazolyl, (J) oxadiazolyl, (K) oxazolyl, (L) pyrazinyl, (M) pyrazolyl, (N) pyridyl, (O) pyrimidyl, (P) pyrrolyl, (Q) quinolyl, (R) tetrazolyl, (S) thiadiazolyl, (T) thiazolyl, (U) thienyl, (V) triazolyl, (W) azetidinyl, (X) 1,4-dioxanyl, (Y) hexahydroazepinyl, (Z) oxanyl, (AA) piperazinyl, (AB) piperidinyl, (AC) pyrrolidinyl, ( AD) tetrahydrofuranyl and (AE) tetrahydrothienyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituents selected from:

(i) Cj 6 alkila, nesubstituiranega ali substituiranega s halo, -CF3, -OCH3 ali fenilom, (ii) C 6 alkoksi, (iii) okso, (iv) hidroksi, (v) tiokso, (vi) -SR9, kjer je R9 kot je definirano zgoraj, (vii) halo, (viii) ciano, (ix) fenila, (x) trifluorometila, (xi) -(CH2)m-NR9R10, kjer je m 0,1 ali 2, in sta R9 in R10, kot je definirano zgoraj, (xii) -NR9COR10, kjer sta R9 in R10, kot je definirano zgoraj, (xiii) -CONR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (xiv) -CO2R9, kjer je R9, kot je definirano zgoraj, in (xv) -(CH2)m-OR9, kjer sta m in R9, kot je definirano zgoraj;(i) C 1-6 alkyl, unsubstituted or substituted with halo, -CF 3 , -OCH 3 or phenyl, (ii) C 6 alkoxy, (iii) oxo, (iv) hydroxy, (v) thioxo, (vi) -SR 9 , wherein R 9 is as defined above, (vii) halo, (viii) cyano, (ix) phenyl, (x) trifluoromethyl, (xi) - (CH 2 ) m -NR 9 R 10 , where m is 0 , 1 or 2, and R 9 and R 10 are as defined above, (xii) -NR 9 COR 10 , where R 9 and R 10 are as defined above, (xiii) -CONR 9 R 10 , where R 9 and R 10 are as defined above, (xiv) -CO 2 R 9 where R 9 is as defined above and (xv) - (CH 2 ) m -OR 9 where m and R 9 as defined above;

(3) C2^ alkenila, nesubstituiranega ali substituiranega z enim ali večimi substituienti, izbranimi iz:(3) C 2 ^ alkenyl, unsubstituted or substituted with one or more substituent selected from:

(a) hidroksi, (b) okso, (c) C16 alkoksi, (d) fenil-Cj 3 alkoksi, (e) fenila, (f) -CN, (g) halo, (h) -CONR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (i) -COR9, kjer je R9, kot je definirano zgoraj, (j) -CO2R9, kjer je R9, kot je definirano zgoraj, (k) heterocikla, kjer je heterocikel’ kot je definirano zgoraj;(a) hydroxy, (b) oxo, (c) C 16 alkoxy, (d) phenyl-C 3 alkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -CONR 9 R 10 , where R 9 and R 10 are as defined above, (i) -COR 9 , where R 9 is as defined above, (j) -CO 2 R 9 , where R 9 is as defined above, (k) a heterocycle wherein the heterocycle is as defined above;

(4) C2 6 alkinila;(4) C 2-6 alkynyl;

(5) fenila, nesubstituiranega ali substituiranega z enim ali večimi izmed substituentov, izbranih iz:(5) phenyl, unsubstituted or substituted by one or more of the substituents selected from:

(a) hidroksi, (b) C16 alkoksi, (c) Cx 6 alkila, (d) C2 5 alkenila, (e) halo, (f) -CN, (g) -no2, (h) -cf3, (i) -(CH2)m-NR9R10, kjer so m, R9 in R10, kot je definirano zgoraj, (j) -NR9COR10, kjer sta R9 in R10, kot je definirano zgoraj, (k) -NR9CO2R10, kjer sta R9 in R10, kot je definirano zgoraj, (l) -CONR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (m) -CO2NR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (n) -COR9, kjer je R9, kot je definirano zgoraj;(a) hydroxy, (b) C 16 alkoxy, (c) C 6 alkyl, (d) C 2 5 alkenyl, (e) halo, (f) -CN, (g) -no 2 , (h) - cf 3 , (i) - (CH 2 ) m -NR 9 R 10 where m, R 9 and R 10 are as defined above, (j) -NR 9 COR 10 , where R 9 and R 10 , as defined above, (k) -NR 9 CO 2 R 10 where R 9 and R 10 are as defined above; (l) -CONR 9 R 10 where R 9 and R 10 are as defined above , (m) -CO 2 NR 9 R 10 , wherein R 9 and R 10 are as defined above, (n) -COR 9 , where R 9 is as defined above;

(o) -CO2R9, kjer je R9, kot je definirano zgoraj;(o) -CO 2 R 9 , wherein R 9 is as defined above;

R2in R3 sta neodvisno izbrana iz skupine, ki sestoji iz:R 2 and R 3 are independently selected from the group consisting of:

(1) vodika, (2) C^ alkila, nesubstituiranega ali substituiranega z enim ali večimi izmed substituentov, izbranih iz:(1) hydrogen, (2) C1-6 alkyl, unsubstituted or substituted by one or more of the substituents selected from:

(a) hidroksi, (b) okso, (c) Cw alkoksi, (d) fenil-Cj 3 alkoksi, (e) fenila, (f) -CN, (g) halo, (h) -NR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (i) -NR9COR10, kjer sta R9 in R10, kot je definirano zgoraj, (j) -NR9CO2R10, kjer sta R9 in R10, kot je definirano zgoraj, (k) -CONR9R1(), kjer sta R9 in R10, kot je definirano zgoraj, (l) -COR9, kjer je R9, kot je definirano zgoraj, (m) -CO2R9, kjer je R9, kot je definirano zgoraj;(a) hydroxy, (b) oxo, (c) C w alkoxy, (d) phenyl-C 1-3 alkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR 9 R 10 , where R 9 and R 10 are as defined above, (i) -NR 9 COR 10 , where R 9 and R 10 are as defined above, (j) -NR 9 CO 2 R 10 , where R 9 and R 10 as defined above, (k) -CONR 9 R 1 () , wherein R 9 and R 10 as defined above, (l) -COR 9 , where R 9 is as defined above , (m) -CO 2 R 9 , wherein R 9 is as defined above;

(3) C2 6 alkenila, nesubstituiranega ali substituiranega z enim ali več izmed substituentov, izbranih iz:(3) C 2-6 alkenyl, unsubstituted or substituted by one or more substituents selected from:

(a) hidroksi, (b) okso, (c) Cx 6 alkoksi, (d) feml-Cx 3 alkoksi, (e) fenila, (0 -CN, (g) halo, (h) -CONR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (i) -COR9, kjer je R9, kot je definirano zgoraj, (j) -CO2R9, kj er j e R9, kot j e definirano zgoraj;(a) hydroxy, (b) oxo, (c) C x 6 alkoxy, (d) phenyl-C x 3 alkoxy, (e) phenyl, (O-CN, (g) halo, (h) -CONR 9 R 10 , wherein R 9 and R 10 are as defined above, (i) -COR 9 , where R 9 is as defined above, (j) -CO 2 R 9 , wherein R 9 is as defined above;

(4) C2 6 alkinila;(4) C 2-6 alkynyl;

(5) fenila, nesubstituiranega ali substituiranega z enim ali več izmed substituentov, izbranih iz:(5) phenyl, unsubstituted or substituted by one or more substituents selected from:

(a) hidroksi, (b) Cw alkoksi, (c) CV6 alkila, (d) C2 5 alkenila, (e) halo, (f) -CN, (g) -no2, (h) -cf3, (i) -(CH2)m-NR9R10, kjer so m, R9 in R10, kot je definirano zgoraj, (j) -NR9COR10, kjer sta R9 in R10, kot je definirano zgoraj, (k) -NR9CO2R10, kjer sta R9 in R10, kot je definirano zgoraj, (l) -CONR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (m) -CO2NR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (n) -COR9, kjer je R9, kot je definirano zgoraj;(a) hydroxy, (b) C w alkoxy, (c) C V6 alkyl, (d) C 2 5 alkenyl, (e) halo, (f) -CN, (g) -no 2, (h) -CF 3 , (i) - (CH 2 ) m -NR 9 R 10 where m, R 9 and R 10 are as defined above, (j) -NR 9 COR 10 , where R 9 and R 10 are as is defined above, (k) -NR 9 CO 2 R 10 , where R 9 and R 10 are as defined above, (l) -CONR 9 R 10 , where R 9 and R 10 are as defined above, (m) -CO 2 NR 9 R 10 , wherein R 9 and R 10 are as defined above, (n) -COR 9 , where R 9 is as defined above;

(o) -CO2R9, kjer je R9, kot je definirano zgoraj;(o) -CO 2 R 9 , wherein R 9 is as defined above;

in skupini R1 in R2 sta lahko združeni skupaj, da tvorita heterocikličen obroč, izbran iz skupine, ki sestoji iz:and the groups R 1 and R 2 may be grouped together to form a heterocyclic ring selected from the group consisting of:

(a) pirolidinila, (b) piperidinila, (c) pirolila, (d) piridinila, (e) imidazolila, (f) oksazolila in (g) tiazolila, in kjer je heterocikličen obroč nesubstituiran ali substituiran z enim ali več substituent(i), izbranimi iz:(a) pyrrolidinyl, (b) piperidinyl, (c) pyrrolyl, (d) pyridinyl, (e) imidazolyl, (f) oxazolyl and (g) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted by one or more substituent (i) ) selected from:

(i) Cj 6 alkila, (ii) okso, (iii) alkoksi, (iv) -NR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (v) halo in (vi) trifluorometila;(i) C 1-6 alkyl, (ii) oxo, (iii) alkoxy, (iv) -NR 9 R 10 , wherein R 9 and R 10 are as defined above, (v) halo and (vi) trifluoromethyl;

in sta lahko skupini R2 in R3 združeni skupaj, da tvorita karbocikličen obroč, izbran iz skupine, ki sestoji iz:and the groups R 2 and R 3 may be grouped together to form a carbocyclic ring selected from the group consisting of:

(a) ciklopentila, (b) cikloheksila, (c) fenila, in kjer je karbocikličen obroč nesubstituiran ali substituiran z enim ali večimi substituenti, izbranimi iz:(a) cyclopentyl, (b) cyclohexyl, (c) phenyl, and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from:

(i) alkila, (ii) alkoksi, (iii) - NR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (iv) halo in (v) trifluorometila;(i) alkyl, (ii) alkoxy, (iii) NR 9 R 10 , wherein R 9 and R 10 are as defined above, (iv) halo and (v) trifluoromethyl;

in sta lahko skupini R2 in R3 združeni skupaj, da tvorita heterocikličen obroč, izbran iz skupine, ki sestoji iz:and the groups R 2 and R 3 may be grouped together to form a heterocyclic ring selected from the group consisting of:

(a) pirolidinila, (b) piperidinila, (c) pirolila, (d) piridinila, (e) imidazolila, (f) furanila, (g) oksazolila, (h) tienila in (i) tiazolila in kjer je heterocikličen obroč nesubsituiran ali substituiran z enim ali več substituenti, izbranimi iz:(a) pyrrolidinyl, (b) piperidinyl, (c) pyrrolyl, (d) pyridinyl, (e) imidazolyl, (f) furanyl, (g) oxazolyl, (h) thienyl and (i) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituents selected from:

(i) C^alkila, (ii) okso, (iii) C j 6alkoksi, (iv) -NR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (v) halo in (vi) trifluorometila;(i) C 1-6 alkyl, (ii) oxo, (iii) C 1-6 alkoxy, (iv) -NR 9 R 10 , wherein R 9 and R 10 are as defined above, (v) halo and (vi) trifluoromethyl;

X je je izbran iz skupine, ki sestoji iz:X is selected from the group consisting of:

(1) -o-, (2) -S-, (3) -SO- in (4) -S02-;(1) -O-, (2) -S-, (3) -SO-, and (4) -S0 2 -;

R4 je izbran iz skupine, ki sestoji iz:R 4 is selected from the group consisting of:

(1)(1)

(2) -Y-C1 8 alkila, kjer je alkil nesubstituiran ali substituiran z enim ali večimi substituenti, izbranimi iz:(2) -YC 18 alkyl, wherein the alkyl is unsubstituted or substituted by one or more substituents selected from:

(a) hidroksi, (b) okso, (c) alkoksi, (d) fenil-C^ 3 alkoksi, (e) fenila, (f) -CN, (g) halo, (h) -NR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (i) -NR9COR10, kjer sta R9 in R10, kot je definirano zgoraj, (j) -NR9CO2R10, kjer sta R9 in R10, kot je definirano zgoraj, (k) -CONR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (l) -COR9, kjer je R9, kot je definirano zgoraj in (m) -CO2R9, kjer je R9, kot je definirano zgoraj;(a) hydroxy, (b) oxo, (c) alkoxy, (d) phenyl-C ^ 3 alkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR 9 R 10, where R 9 and R 10 are as defined above, (i) -NR 9 COR 10 where R 9 and R 10 are as defined above; (j) -NR 9 CO 2 R 10 where R 9 and R 10 as defined above, (k) -CONR 9 R 10 where R 9 and R 10 are as defined above, (l) -COR 9 where R 9 is as defined above and (m ) -CO 2 R 9 , wherein R 9 is as defined above;

(3) - Y-C2 c alkenila, kjer je alkenil nesubstituiran ali substituiran z enim ali več izmed substituentov, izbranimi iz:(3) - YC 2 c alkenyl, wherein the alkenyl is unsubstituted or substituted by one or more substituents selected from:

(a) hidroksi, (b) okso, (c) alkoksi, (d) fenil-Cj 3 alkoksi, (e) fenila, (f) -CN, (g) halo, (h) -CONR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (i) -COR9, kjer je R9, kot je definirano zgoraj, (j) -CO2R9, kjer je R9, kot je definirano zgoraj;(a) hydroxy, (b) oxo, (c) alkoxy, (d) phenyl-C 3 alkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -CONR 9 R 10, wherein R 9 and R 10 are as defined above, (i) -COR 9 , wherein R 9 is as defined above, (j) -CO 2 R 9 , wherein R 9 is as defined above;

(4) -O(CO)-fenila, kjer je fenil substituiran ali nesubstituiran z enim ali več izmed R6, R7 in R8;(4) -O (CO) -phenyl, wherein the phenyl is substituted or unsubstituted by one or more of R 6 , R 7 and R 8 ;

Rs je izbran iz skupine, ki sestoji iz:R s is selected from the group consisting of:

(1) fenila, nesubstituiranega ali substituiranega z enim ali večimi izmed R11, R12in R13;(1) phenyl, unsubstituted or substituted by one or more of R 11 , R 12 and R 13 ;

(2) Cx g alkila, nesubstituiranega ali substituiranega z enim ali večimi izmed substituentov, izbranimi iz:(2) C xg alkyl, unsubstituted or substituted by one or more of the substituents selected from:

(a) hidroksi, (b) okso, (c) Cj 6 alkoksi, (d) fenil-C13 alkoksi, (e) fenila, (f) -CN, (g) halo, (h) -NR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (i) -NR9COR10, kjer sta R9 in R10, kot je definirano zgoraj, (j) -NR9CO2R10, kjer sta R9 in R10, kot je definirano zgoraj, (k) -CONR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (l) -COR9, kjer je R9, kot je definirano zgoraj in (m) -CO2R9, kjer je R9, kot je definirano zgoraj;(a) hydroxy, (b) oxo, (c) C 1-6 alkoxy, (d) phenyl-C 13 alkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR 9 R 10 , where R 9 and R 10 are as defined above, (i) -NR 9 COR 10 , where R 9 and R 10 are as defined above, (j) -NR 9 CO 2 R 10 , where R 9 and R 10 as defined above, (k) -CONR 9 R 10 where R 9 and R 10 are as defined above, (l) -COR 9 where R 9 is as defined above and ( m) -CO 2 R 9 , wherein R 9 is as defined above;

(3) C26 alkenila nesubstituiranega ali substituiranega z enim ali večimi izmed substituentov, izbranimi iz:(3) C 26 alkenyl unsubstituted or substituted by one or more of the substituents selected from:

(a) hidroksi, (b) okso, (c) Cu alkoksi, (d) fenil-Cj 3 alkoksi, (e) fenila, (f) -CN, (g) halo, (h) -CONR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (i) -COR9, kjer je R9, kot je definirano zgoraj, (j) -CO2R9, kjer je R9, kot je definirano zgoraj;(a) hydroxy, (b) oxo, (c) C in alkoxy, (d) phenyl-C 3 alkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -CONR 9 R 10 , wherein R 9 and R 10 are as defined above, (i) -COR 9 , wherein R 9 is as defined above, (j) -CO 2 R 9 , wherein R 9 is as defined above;

(4) heterocikla, pri čemer je heterocikel, kot je definirano zgoraj:(4) heterocycle, wherein the heterocycle is as defined above:

R6, R7 in R8 neodvisno izberemo iz skupine, ki sestoji iz:R 6 , R 7 and R 8 are independently selected from the group consisting of:

(1) (1) vodika; hydrogen; (2) (2) C^ alkila, nesubstituiranega ali substituiranega z enim ali večimi substituenti, izbranimi iz: (a) hidroksi, (b) okso, (c) C16 alkoksi, (d) fenil-C13 alkoksi, (e) fenila, (f) -CN, (g) halo, (h) -NR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (i) -NR9COR10, kjer sta R9 in R10, kot je definirano zgoraj, (j) -NR9CO2R10, kjer sta R9 in R10, kot je definirano zgoraj, (k) -CONR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (l) -COR9, kjer je R9, kot je definirano zgoraj in (m) -CO2R9, kjer je R9, kot je definirano zgoraj;C 1-6 alkyl unsubstituted or substituted by one or more substituents selected from: (a) hydroxy, (b) oxo, (c) C 16 alkoxy, (d) phenyl-C 13 alkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR 9 R 10 where R 9 and R 10 are as defined above, (i) -NR 9 COR 10 where R 9 and R 10 are as defined above, (j) -NR 9 CO 2 R 10 where R 9 and R 10 are as defined above, (k) -CONR 9 R 10 where R 9 and R 10 are as defined above, (l ) -COR 9 , wherein R 9 is as defined above and (m) -CO 2 R 9 where R 9 is as defined above; (3) (3) C2 6 alkenila, nesubstituiranega ali substituiranega z enim ali večimiC 2 6 alkenyl, unsubstituted or substituted by one or more

substituenti, izbranimi iz:substituents selected from:

(a) hidroksi, (b) okso, (c) alkoksi, (d) fenil-C13 alkoksi, (e) fenila, (f) -CN, (g) halo, (h) -CONR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (i) -COR9, kjer je R9, kot je definirano zgoraj in Q) -CO2R9, kjer je R9, kot je definirano zgoraj;(a) hydroxy, (b) oxo, (c) alkoxy, (d) phenyl-C 13 alkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -CONR 9 R 10 , where R 9 and R 10 are as defined above, (i) -COR 9 wherein R 9 is as defined above and Q) -CO 2 R 9 wherein R 9 is as defined above;

(4) C26 alkinila;(4) C 26 alkynyl;

(5) fenila, nesubstituiranega ali substituiranega z enim ali večimi sub stituenti, izbranimi iz:(5) phenyl, unsubstituted or substituted by one or more substituents selected from:

(a) (a) hidroksi, hydroxy, (b) (b) Cx 6 alkoksi,C x 6 alkoxy, (c) (c) CT 6 alkila,C 6 alkyl, (d) (d) C2 5 alkenila,C 2 5 alkenyl, (e) (e) halo, hello, (C (C -CN, -CN, (g) (g) -no2,-no 2 , (h) (h) -cf3,-cf 3 , (i) (i) -(CH2)m-NR9R10, kjer so m, R9 in R10, kot je definirano zgoraj,- (CH 2 ) m -NR 9 R 10 , wherein m, R 9 and R 10 are as defined above, (j) (j) -NR9COR10, kjer sta R9 in R10, kot je definirano zgoraj,-NR 9 COR 10 , wherein R 9 and R 10 are as defined above, (k) (k) -NR9CO2R10, kjer sta R9 in R10, kot je definirano zgoraj,-NR 9 CO 2 R 10 , wherein R 9 and R 10 are as defined above, (D (D -CONR9R10, kjer sta R9 in R10, kot je definirano zgoraj,-CONR 9 R 10 , wherein R 9 and R 10 are as defined above, (m) (m) -CO2NR9R10, kjer sta R9 in R10, kot je definirano zgoraj,-CO 2 NR 9 R 10 , wherein R 9 and R 10 are as defined above, (n) (n) -COR9, kjer je R9, kot je definirano zgoraj,-COR 9 , wherein R 9 is as defined above, (o) (o) -CO2R9, kjer je R9, kot je definirano zgoraj;-CO 2 R 9 , wherein R 9 is as defined above; (6) (6) halo, hello, (7) (7) -CN, -CN, (8) (8) -cf3,-cf 3 , (9) (9) -no2,-no 2 , (10) (10) -SR14, kjer je R14 vodik ali C^alkil,-SR 14 where R 14 is hydrogen or C 1-6 alkyl,

(11) -SOR14, kjer je R14, kot je definirano zgoraj, (12) -SO2R14, kjer je R14, kot je definirano zgoraj, (13) NR9COR10, kjer sta R9 in R10, kot je definirano zgoraj, (14) CONR9COR10, kjer sta R9 in R10, kot je definirano zgoraj, (15) NR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (16) NR9CO2R10, kjer sta R9 in R10, kot je definirano zgoraj, (17) hidroksi, (18) Cj ^alkoksi, (19) COR9, kjer je R9, kot je definirano zgoraj, (20) CO2R9, kjer je R9, kot je definirano zgoraj;(11) -SOR 14 , where R 14 is as defined above, (12) -SO 2 R 14 , where R 14 is as defined above, (13) NR 9 COR 10 , where R 9 and R 10 , as defined above, (14) CONR 9 COR 10 , wherein R 9 and R 10 are as defined above, (15) NR 9 R 10 , where R 9 and R 10 are as defined above, ( 16) NR 9 CO 2 R 10 , wherein R 9 and R 10 are as defined above, (17) hydroxy, (18) C 1-6 alkoxy, (19) COR 9 , where R 9 is as defined above, (20) CO 2 R 9 , wherein R 9 is as defined above;

R11, R12 in R13 so neoodvisno izbrani iz definicij R6, R7 in R8;R 11 , R 12 and R 13 are independently selected from the definitions R 6 , R 7 and R 8 ;

Y je izbran iz skupine, ki sestoji iz:Y is selected from the group consisting of:

(1) enojne vezi, (2) -O-, (3) -S-, (4) -CO-, (5) -CH2-, (6) -CHR15- in (7) -CRl5R16-, kjer sta R15 in R16 neodvisno izbrana iz skupine, ki sestoji iz:(1) single bonds, (2) -O-, (3) -S-, (4) -CO-, (5) -CH 2 -, (6) -CHR 15 - and (7) -CR 15 R 16 -, wherein R 15 and R 16 are independently selected from the group consisting of:

(a) C16 alkila, nesubstituiranega ali substituiranega z enim ali večimi izmed substituentov, izbranih iz:(a) C 16 alkyl unsubstituted or substituted by one or more of the substituents selected from:

(i) hidroksi, (ii) okso, (iii) alkoksi, (iv) fenil-Cj 3 alkoksi, (v) fenila, (vi) -CN, (vii) halo, (viii) -NR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (ix) -NR9COR10, kjer sta R9 in R10, kot je definirano zgoraj, (x) -NR9CO2R10, kjer sta R9 in R10, kot je definirano zgoraj, (xi) -CONR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (xii) -COR9, kjer je R9, kot je definirano zgoraj in (xiii) -CO2R9, kjer je R9, kot je definirano zgoraj;(i) hydroxy, (ii) oxo, (iii) alkoxy, (iv) phenyl-C 3 alkoxy, (v) phenyl, (vi) -CN, (vii) halo, (viii) -NR 9 R 10, wherein R 9 and R 10 are as defined above, (ix) -NR 9 COR 10 , where R 9 and R 10 are as defined above, (x) -NR 9 CO 2 R 10 , where R 9 and R 10 as defined above, (xi) -CONR 9 R 10 where R 9 and R 10 are as defined above, (xii) -COR 9 where R 9 is as defined above and (xiii) -CO 2 R 9 , wherein R 9 is as defined above;

(b) fenila, nesubstituiranega ali substituiranega z enim ali večimi izmed substituentov, izbranih ih:(b) phenyl, unsubstituted or substituted by one or more of the substituents selected from them:

(i) hidroksi, (ii) alkoksi, (iii) alkila, (iv) C2 5 alkenila, (v) halo, (vi) -CN, (vii) -NO2, (viii) -CF3, (ix) -(CH2)m-NR9R10, kjer so m, R9 in R10, kot je definirano zgoraj, (x) -NR9COR10, kjer sta R9 in R10, kot je definirano zgoraj, (xi) -NR9CO2R10, kjer sta R9 in R10, kot je definirano zgoraj, (xii) -CONR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (xiii) -CO2NR9R10, kjer sta R9 in R10, kot je definirano zgoraj, (xiv) -COR9, kjer je R9, kot je definirano zgoraj, in (xv) -CO2R9, kjer je R9, kot je definirano zgoraj;(i) hydroxy, (ii) alkoxy, (iii) alkyl, (iv) C 2 5 alkenyl, (v) halo, (vi) -CN, (vii) -NO 2 , (viii) -CF 3 , (ix ) - (CH 2 ) m -NR 9 R 10 where m, R 9 and R 10 are as defined above, (x) -NR 9 COR 10 , where R 9 and R 10 are as defined above, (xi) -NR 9 CO 2 R 10 , wherein R 9 and R 10 are as defined above, (xii) -CONR 9 R 10 , where R 9 and R 10 are as defined above, (xiii) - CO 2 NR 9 R 10 where R 9 and R 10 are as defined above, (xiv) -COR 9 where R 9 is as defined above and (xv) -CO 2 R 9 where R is 9 as defined above;

Z je izbran iz:Z is selected from:

(1) vodika, (2) C1-4 alkila in (3) hidroksi, s pridržkom, da če je Y -0-, potem je Z drugačen kot hidroksi, ali če je Y -CHR15-, potem sta lahko Z in R15 združena skupaj, da tvorita dvojno vez.(1) hydrogen, (2) C 1-4 alkyl and (3) hydroxy, with the proviso that if Y is -O- then Z is different from hydroxy, or if Y is -CHR 15 - then Z can be and R 15 joined together to form a double bond.

Spojine v smislu predloženega izuma imajo asimetrične centre in predloženi izum vključuje vse optične izomere in njihove zmesi.The compounds of the present invention have asymmetric centers and the present invention includes all optical isomers and mixtures thereof.

Poleg tega se lahko spojine z ogljik-ogljik dvojnimi vezmi pojavijo v Z- in E-oblikah z vsemi izomernimi oblikami spojin, ki so vključene v predloženi izum.In addition, carbon-carbon double bond compounds can occur in the Z- and E-forms with all the isomeric forms of the compounds included in the present invention.

Kadar se katerakoli spremenljivka (npr. alkil, aril, R6, R7, R8, R9, R10, R11, R12, R13, itd.) pojavi več kot enkrat v katerikoli spremenljivki ali v formuli I, je njena definicija pri vsakokratnem pojavljanju neodvisna od njene definicije pri katerem koli drugem pojavljanju.When any variable (e.g., alkyl, aryl, R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , etc.) occurs more than once in any variable or formula I, its definition at each occurrence is independent of its definition at any other occurrence.

Kot uporabljamo tukaj, izraz alkil vključuje tiste alkilne skupine določenega števila ogljikovih atomov, ali nerazvejane, razvejane ali ciklične konfiguracije. Primeri alkila vključujejo metil, etil, propil, izopropil, butil, izo-, sek- in terc-butil, pentil, heksil, heptil, 3-etilbutil, ciklopropil, ciklobutil, ciklopentil, cikloheksil, cikloheptil, norbornil in podobne. Alkoksi predstavlja alkilno skupino določenega števila ogljikovih atomov, ki so vezani preko kisikovega mostu, kot je metoksi, etoksi, propoksi, butoksi in pentoksi. Alkenil je mišljen, da vključuje ogljikovodične verige določenega števila ogljikovih atomov, ali nerazvejene- ali razvejane- konfiguracije in vsaj eno nenasičenost, ki se lahko pojavi na katerem koli mestu vzdolž verige, kot so etenil, propenil, butenil, pentenil, dimetilpentil in podobni, in kjer je uporabno, vključuje E in Z oblike. Halogen ali halo, kot uporabljamo tukaj, pomeni fluoro, kloro, bromo in jodo.As used herein, the term alkyl includes those alkyl groups of a certain number of carbon atoms, or unbranched, branched or cyclic configurations. Examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and the like. Alkoxy represents an alkyl group of a certain number of carbon atoms bonded through an oxygen bridge, such as methoxy, ethoxy, propoxy, butoxy and pentoxy. Alkenyl is intended to include hydrocarbon chains of a specified number of carbon atoms, or unbranched or branched configuration and at least one unsaturation which may occur at any site along the chain such as ethenyl, propenyl, butenyl, pentenyl, dimethylpentyl and the like, and where applicable, includes E and Z forms. Halogen or halo as used herein means fluoro, chloro, bromo and iodo.

Izraz aril pomeni fenil ali naftil, ali nesubstituiran ali substituiran z enim, dvema ali tremi substituenti, izbranimi iz skupine, ki sestoji iz halo, Cx 4-alkila, C4 4-alkoksi, NO2, CF3, C14-alkiltio, OH, -N(R6)2, -CO2R6, Cx 4-perfluoroalkila, C3 6perfluorocikloalkila in tetrazol-5-ila.The term aryl means phenyl or naphthyl, or unsubstituted or substituted by one, two or three substituents selected from the group consisting of halo, C x 4 -alkyl, C 4 4 -alkoxy, NO 2 , CF 3 , C 14 -alkylthio , OH, -N (R 6 ) 2, -CO 2 R 6 , Cx 4-perfluoroalkyl, C 3 6 perfluorocycloalkyl and tetrazol-5-yl.

Izraz heteroaril pomeni nesubstituiran, monosubstituiran ali disubstituiran pet ali šest členski aromatski heterocikel, ki vključuje od 1 do 3 heteroatome, izbrane iz skupine, ki sestoji iz O, N in S, in kjer so substituenti člani izbrani iz skupine, ki sestoji iz -OH, -SH, -CM-alkila, -C14alkoksi, -CF3, halo, -NO2, -CO2R9, -N(R9R10) in kondenzirane benzo skupine.The term heteroaryl means unsubstituted, monosubstituted or disubstituted five or six membered aromatic heterocycle comprising from 1 to 3 heteroatoms selected from the group consisting of O, N and S, and wherein the substituent members are selected from the group consisting of -OH , -SH, -C M -alkyl, -C 14 alkoxy, -CF 3 , halo, -NO 2 , -CO 2 R 9 , -N (R 9 R 10 ) and fused benzo groups.

Kot bodo razumeli strokovnjaki, farmacevtsko sprejemljive soli vključujejo, toda neomejeno, soli z anorganskimi kislinami, kot so klorovodikova, sulfatna, fosfatna, difosfatna, bromovodikova in nitratna, ali soli z organskimi kislinami, kot je malat, maleat, fumarat, tartrat, sukcinat, citrat, acetat, laktat, metansulfonat, p-toluensulfonat, 2-hidroksietilsulfonat, pamoat, salicilat in stearat. Podobno farmacevtsko sprejemljivi kationi vključujejo, toda neomejeno, natrij, kalij, kalcij, aluminij, litij in amonij.As will be understood by those skilled in the art, pharmaceutically acceptable salts include, but are not limited to, salts with inorganic acids such as hydrochloric, sulphate, phosphate, diphosphate, hydrobromic and nitric, or salts with organic acids such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, pamoate, salicylate and stearate. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium and ammonium.

V spojinah s formulo I je prednostno, daje:In the compounds of formula I, it is preferred that:

R1 izbran iz skupine, ki sestoji iz:R 1 selected from the group consisting of:

(1) C alkila, substituiranega z enim ali večimi substituenti, izbranih iz:(1) C alkyl substituted with one or more substituents selected from:

(a) heterocikla, kjer je heterocikel izbran iz skupine, ki sestoji iz:(a) a heterocycle, wherein the heterocycle is selected from the group consisting of:

(A) benzimidazolila, (B) imidazolila, (C) izoksazolila, (D) izotiazolila, (E) oksadiazolila, (F) pirazinila, (G) pirazolila, (H) piridila, (I) pirolila, (J) tetrazolila, (K) tiadiazolila, (L) triazolila in (M) piperidinila, in kjer je heterocikel nesubstituiran ali substituiran z enim ali večimi substituenti, izbranimi iz:(A) benzimidazolyl, (B) imidazolyl, (C) isoxazolyl, (D) isothiazolyl, (E) oxadiazolyl, (F) pyrazinyl, (G) pyrazolyl, (H) pyridyl, (I) pyrrolyl, (J) tetrazolyl, (K) thiadiazolyl, (L) triazolyl and (M) piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituents selected from:

(i) alkila, nesubstituiranega ali substituiranega s halo, -CF3, -OCH3 ali fenilom, (ii) alkoksi, (iii) okso, (iv) tiokso, (v) ciano, (vi) -SCH3, (vii) fenila, (viii) hidroksi, (ix) trifluorometila, (x) -(CH2)m-NR9R10, kjer je m 0, 1 ali 2, in sta R9 in R10 neodvisno izbrana iz:(i) alkyl unsubstituted or substituted with halo, -CF 3 , -OCH 3 or phenyl, (ii) alkoxy, (iii) oxo, (iv) thioxo, (v) cyano, (vi) -SCH 3 , (vii ) phenyl, (viii) hydroxy, (ix) trifluoromethyl, (x) - (CH 2 ) m -NR 9 R 10 , where m is 0, 1 or 2, and R 9 and R 10 are independently selected from:

(I) vodika, (II) alkila, (III) hidroksi-C1 alkila in (IV) fenila, (xi) -NR9COR10, kjer sta R9 in R10, kot je definirano zgoraj, (xii) -CONR9R10, kjer sta R9 in R10, kot je definirano zgoraj;(I) hydrogen, (II) alkyl, (III) hydroxy-C 1 alkyl, and (IV) phenyl, (xi) -NR 9 COR 10 , wherein R 9 and R 10 are as defined above, (xii) - CONR 9 R 10 , wherein R 9 and R 10 are as defined above;

R2 in R3 sta neodvisno izbrana iz skupine, ki sestoji iz:R 2 and R 3 are independently selected from the group consisting of:

(1) vodika, (2) Cx 6 alkila, (3) C2 6 alkenila in (4) fenila;(1) hydrogen, (2) C x 6 alkyl, (3) C 2 6 alkenyl and (4) phenyl;

Xje-O-;X is -O-;

R4je:R 4 is:

(1)(1)

R5 je fenil, nesubstituiran ali substituiran s halo;R 5 is phenyl, unsubstituted or substituted with halo;

R6, R7 in R8 so neodvisno izbrani iz skupine, ki sestoji iz:R 6 , R 7 and R 8 are independently selected from the group consisting of:

(1) vodika, (2) alkila, (3) halo in (4) -CF3;(1) hydrogen, (2) alkyl, (3) halo, and (4) -CF 3 ;

Y je -O-; inY is -O-; and

Z je vodik ali C14 alkil.Z is hydrogen or C 14 alkyl.

Izvedba novih spojin v smislu predloženega izuma je tista, kjer je X O, R4 -YCHZ fenil, in R5 fenil, s strukturno formulo:An embodiment of the new compounds of the present invention is one where XO, R 4 -YCHZ is phenyl, and R 5 is phenyl, having the structural formula:

p6p6

ali njihova farmacevtsko sprejemljiva sol, kjer so R1, R2, R3, R6, R7, R8, R11, R12, R13 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13

Υ in Z, kot je definirano zgoraj.Υ and Z as defined above.

Še ena izvedba novih spojin v smislu predloženega izuma je tista, kjer je X S, R4 -Y-CHZ-fenil in R5 fenil s strukturno formulo:Another embodiment of the new compounds of the present invention is one where XS, R 4 is -Y-CHZ-phenyl and R 5 is phenyl of the structural formula:

ali njihova farmacevtsko sprejemljiva sol, kjer so R1, R2, R3, R6, R7, R8, R11, R12, R13, Y in Z, kot je definirano zgoraj.or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , Y and Z are as defined above.

Še ena izvedba novih spojin v smislu predloženega izuma je tista, kjer je X SO, R4 -Y-CHZ-fenil in R5 fenil s strukturno formulo:Another embodiment of the new compounds of the present invention is one where X is SO, R 4 is -Y-CHZ-phenyl and R 5 is phenyl of the structural formula:

ali njihova farmacevtsko sprejemljiva sol, kjer so R1, R2, R3, R6, R7, R8, R11, R12, R13, Y in Z, kot je definirano zgoraj.or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , Y and Z are as defined above.

Še ena izvedba novih spojin v smislu predloženega izuma je tista, kjer je X SO2, R4 -Y-CHZ-fenil in R5 fenil s strukturno formulo:Another embodiment of the new compounds of the present invention is one where X is SO 2 , R 4 is -Y-CH 2 -phenyl and R 5 is phenyl of the structural formula:

ali njihova farmacevtsko sprejemljiva sol, kjer so R1, R2, R3, R6, R7, R8, R11, R12, R13, Y in Z, kot je definirano zgoraj.or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , Y and Z are as defined above.

V spojinah predloženega izuma je prednostna izvedba tista, v kateri je R1 izbran iz naslednje skupine substituentov:In the compounds of the present invention, a preferred embodiment is one in which R 1 is selected from the following group of substituents:

Specifične spojine znotraj obsega predloženega izuma vključujejo:Specific compounds within the scope of the present invention include:

1) (+/-)-2-(3,5-bis(trifluorometil)benziloksi)-3-fenil-morfolin;1) (+/-) - 2- (3,5-bis (trifluoromethyl) benzyloxy) -3-phenyl-morpholine;

2) (2R,S)-(3,5-bis(trifluorometil)benziloksi)-(3R)-fenil-(6R)-metil-morfolin;2) (2R, S) - (3,5-bis (trifluoromethyl) benzyloxy) - (3R) -phenyl- (6R) -methyl-morpholine;

3) (2R,S)-(3,5-bis(trifluorometil)benziloksi)-(3S)-fenil-(6R)-metil-morfolin;3) (2R, S) - (3,5-bis (trifluoromethyl) benzyloxy) - (3S) -phenyl- (6R) -methyl-morpholine;

4) (+/-)-2-(3,5-bis(trifluorometil)benziloksi)-3-fenil-4-metilkarboksamidomorfolin;4) (+/-) - 2- (3,5-bis (trifluoromethyl) benzyloxy) -3-phenyl-4-methylcarboxamidomorpholine;

5) (+/-)-2-(3,5-bis(trifluorometil)benziloksi)-3-fenil-4-metoksi-karbonilmetilmorfolin;5) (+/-) - 2- (3,5-bis (trifluoromethyl) benzyloxy) -3-phenyl-4-methoxy-carbonylmethylmorpholine;

6) 2-(2-(3,5-bis(trifluorometil)fenil)etenil)-3-fenil-5-okso-morfolin;6) 2- (2- (3,5-bis (trifluoromethyl) phenyl) ethenyl) -3-phenyl-5-oxo-morpholine;

7) 3-fenil-2-(2-(3,5-bis(trifluorometil)fenil)-etil)-morfolin;7) 3-phenyl-2- (2- (3,5-bis (trifluoromethyl) phenyl) -ethyl) -morpholine;

8) 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-6-(S)-metil-morfolin;8) 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-6- (S) -methyl-morpholine;

9) 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-6-(S)-metil-morfolin;9) 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-6- (S) -methyl-morpholine;

10) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)fenil-6-(S)-metil-morfolin;10) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) phenyl-6- (S) -methyl-morpholine;

11) 2-(S)-(3,5-bis(trifIuorometil)benziloksi)-3-(S)-fenil-6-(S)-metil-morfolin;11) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-6- (S) -methyl-morpholine;

12) 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(R)-metil-morfolin;12) 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-5- (R) -methyl-morpholine;

13) 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(R)-metil-morfolin;13) 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (R) -methyl-morpholine;

14) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(R)-metil-morfolin;14) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-5- (R) -methyl-morpholine;

15) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(R)-metil-morfolin;15) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (R) -methyl-morpholine;

16) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenilmorfolin;16) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenylmorpholine;

17) 4-(3-(1,2,4-triazolo)metil)-2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil morfolin;17) 4- (3- (1,2,4-triazolo) methyl) -2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl morpholine;

18) 4-(3-(5-okso-lH,4H-l,2,4-triazolo)metil)-2-(S)-(3,5-bis(trifluorometil) benziloksi)-3-(S)-fenil-morfolin;18) 4- (3- (5-oxo-1H, 4H-1,2,4-triazolo) methyl) -2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-morpholine;

19) 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-6-(R)-metil-morfolin;19) 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-6- (R) -methyl-morpholine;

20) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-6-(R)-metil-morfolin;20) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-6- (R) -methyl-morpholine;

21) 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-6-(R)-metil-morfolin;21) 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-6- (R) -methyl-morpholine;

22) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-6-(R)-metil-morfolin;22) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-6- (R) -methyl-morpholine;

23) 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(S)-metil-morfolin;23) 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (S) -methyl-morpholine;

24) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(S)-metil-morfolin;24) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (S) -methyl-morpholine;

25) 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(S)-metil-morfolin;25) 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-5- (S) -methyl-morpholine;

26) 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(R)-fenil-morfolin;26) 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (R) -phenyl-morpholine;

27) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(R)-fenil-morfolin;27) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (R) -phenyl-morpholine;

28) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(S)-fenil-morfolm;28) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-5- (S) -phenyl-morpholine;

29) 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(S)-fenil-morfolin;29) 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-5- (S) -phenyl-morpholine;

30) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-6-(R)-metil-3-(S)-fenil-4-(3-(l,2,4triazolo)metil)-morfolin;30) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -6- (R) -methyl-3- (S) -phenyl-4- (3- (1,2,4triazolo) methyl) -morpholine;

31) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-6-(R)-metil-4-(3-(5-okso- 1H,4H l,2,4-triazolo)rnetil)-3-(S)-fenil-niorfolin;31) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -6- (R) -methyl-4- (3- (5-oxo-1H, 4H 1,2,4-triazolo) propyl ) -3- (S) -phenyl-niorfoline;

32) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-morfolin;32) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-morpholine;

33) 4-(3-(1,2,4-triazolo)metil)-2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)fenil-morfolin;33) 4- (3- (1,2,4-triazolo) methyl) -2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) phenyl-morpholine;

34) 4-(3-(5-okso-lH,4H-l,2,4-triazolo)metil)-2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-morfolin;34) 4- (3- (5-Oxo-1H, 4H-1,2,4-triazolo) methyl) -2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-morpholine;

35) 4-(2-(imidazolo)metil)-2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenilmorfolin;35) 4- (2- (imidazolo) methyl) -2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenylmorpholine;

36) 4-(4-imidazolo)metil)-2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenilmorfolin;36) 4- (4-imidazolo) methyl) -2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenylmorpholine;

37) 4-(aminokarbonilmetil)-2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenilmorfolin;37) 4- (aminocarbonylmethyl) -2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenylmorpholine;

38) 4-(2-(imidazolo)metil-2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenilmorfolin;38) 4- (2- (imidazolo) methyl-2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenylmorpholine;

39) 4-(4(imidazolo)metil)-2-(S)-(3,5-bis(trifluorometil)benziloksi-3-(S)-fenilmorfolin;39) 4- (4 (imidazolo) methyl) -2- (S) - (3,5-bis (trifluoromethyl) benzyloxy-3- (S) -phenylmorpholine;

40) 4-(2-(imidazolo)metil)-2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-6 (R) -metil-morfolin;40) 4- (2- (imidazolo) methyl) -2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-6 (R) -methyl-morpholine;

41) 4-(4-(imidazolo)metil)-2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil6-(R)-metil-morfolin;41) 4- (4- (imidazolo) methyl) -2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl6- (R) -methyl-morpholine;

42) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-((6-hidroksi)heksil)-3-(R)-fenilmorfolin;42) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4 - ((6-hydroxy) hexyl) -3- (R) -phenylmorpholine;

43) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-(5-(metilaminokarbonil)pentil) -3-(R)-fenil-morfolin;43) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (5- (methylaminocarbonyl) pentyl) -3- (R) -phenyl-morpholine;

44) 4-(3-(1,2,4-triazolo)metil)-2-(3,5-dimetilbenziloksi)-3-fenil-morfolin;44) 4- (3- (1,2,4-triazolo) methyl) -2- (3,5-dimethylbenzyloxy) -3-phenyl-morpholine;

45) 4-(3-(5-okso-lH,4H-l,2,4-triazolo)metil)-2-(3,5-dimetil)benziloksi)-3-fenilmorfolin;45) 4- (3- (5-oxo-1H, 4H-1,2,4-triazolo) methyl) -2- (3,5-dimethyl) benzyloxy) -3-phenylmorpholine;

46) 4-(3-(1,2,4-triazolo)metil-2-(3,5-di(terc.-butil)-benziloksi)-3-fenil-morfolin;46) 4- (3- (1,2,4-triazolo) methyl-2- (3,5-di (tert-butyl) -benzyloxy) -3-phenyl-morpholine;

47) 4-(3-(5-okso-lH,4H-l,2,4-triazolo)metil)-2-(3,5-di(terc.-butil)benziloksi)3-fenil-morfolin;47) 4- (3- (5-oxo-1H, 4H-1,2,4-triazolo) methyl) -2- (3,5-di (tert-butyl) benzyloxy) 3-phenyl-morpholine;

48) 4-(3-(1,2,4-triazolo)metil)-2-(3-terc.-butil)-5-metilbenziloksi)-3-fenil-morfolin;48) 4- (3- (1,2,4-triazolo) methyl) -2- (3-tert-butyl) -5-methylbenzyloxy) -3-phenyl-morpholine;

49) 4-(3-(5-okso-lH,4H-l,2,4-triazolo)metil)-2-(3-(terc.-butil)-5-metilbenziloksi)3-fenil-morfolin;49) 4- (3- (5-oxo-1H, 4H-1,2,4-triazolo) methyl) -2- (3- (tert-butyl) -5-methylbenzyloxy) 3-phenyl-morpholine;

50) 4-(3-(1,2,4-triazolo)metil)-2-(3-(trifluorometil)-5-metilbenziloksi)-3-fenilmorfolin;50) 4- (3- (1,2,4-triazolo) methyl) -2- (3- (trifluoromethyl) -5-methylbenzyloxy) -3-phenylmorpholine;

51) 4-(3-(5-okso-lH,4H-l,2,4-triazolo)metil)-2-(3-(trifluorometil)-5-metilbenziloksi)-3-fenil-morfolin;51) 4- (3- (5-oxo-1H, 4H-1,2,4-triazolo) methyl) -2- (3- (trifluoromethyl) -5-methylbenzyloxy) -3-phenyl-morpholine;

52) 4-(3-(1,2,4-triazolo)metil)-2-(3-(terc.-butil)-5-(trifluorometil)benziloksi)-3fenil-morfolin;52) 4- (3- (1,2,4-triazolo) methyl) -2- (3- (tert-butyl) -5- (trifluoromethyl) benzyloxy) -3-phenyl-morpholine;

53) 4-(3-(5-okso-lH,4H-l,2,4-triazolo)metil)-2-(3-(terc.-butil)-5-(trifluorometil) benziloksi)-3-fenil-morfolin;53) 4- (3- (5-oxo-1H, 4H-1,2,4-triazolo) methyl) -2- (3- (tert-butyl) -5- (trifluoromethyl) benzyloxy) -3-phenyl -morpholine;

54) 4-(2-(imidazolo)metil)-2-(3,5-dimetilbenziloksi)-3-fenil-morfolin;54) 4- (2- (imidazolo) methyl) -2- (3,5-dimethylbenzyloxy) -3-phenyl-morpholine;

55) 4-(4-(imidazolo)metil)-2-(3,5-dimetilbenziloksi)-3-fenil-morfolin;55) 4- (4- (imidazolo) methyl) -2- (3,5-dimethylbenzyloxy) -3-phenyl-morpholine;

56) 4-(2-(imidazolo)metil)-2-(3,5-di(terc.-butil)-benziloksi)-3-fenil-morfolin;56) 4- (2- (imidazolo) methyl) -2- (3,5-di (tert-butyl) -benzyloxy) -3-phenyl-morpholine;

57) 4-(4-(imidazolo)metil)-2-(3,5-di(terc.-butil)-benziloksi)-3-fenil-morfolin;57) 4- (4- (imidazolo) methyl) -2- (3,5-di (tert-butyl) -benzyloxy) -3-phenyl-morpholine;

58) 4-(2-(imidazolo)metil)-2-(3-terc.-butil)-5-metilbenziloksi)-3-fenil-morfolin;58) 4- (2- (imidazolo) methyl) -2- (3-tert-butyl) -5-methylbenzyloxy) -3-phenyl-morpholine;

59) 4-(4-(imidazolo)metil)-2-(3-(terc.-butil)-5-metilbenziloksi)-3-fenil-morfolin;59) 4- (4- (imidazolo) methyl) -2- (3- (tert-butyl) -5-methylbenzyloxy) -3-phenyl-morpholine;

60) 4-(2-(imidazolo)metil)-2-(3-(trifluorometil)-5-metilbenziloksi)-3-fenilmorfolin;60) 4- (2- (imidazolo) methyl) -2- (3- (trifluoromethyl) -5-methylbenzyloxy) -3-phenylmorpholine;

61) 4-(4-(imidazolo)metil)-2-(3-trifluorometil)-5-metilbenziloksi)-3-fenilmorfolin;61) 4- (4- (imidazolo) methyl) -2- (3-trifluoromethyl) -5-methylbenzyloxy) -3-phenylmorpholine;

62) 4-(2-(imidazolo)metil)-2-(3-(terc.-butil)-5-(trifluorometil)benziloksi)-3fenil-morfolin;62) 4- (2- (imidazolo) methyl) -2- (3- (tert-butyl) -5- (trifluoromethyl) benzyloxy) -3-phenyl-morpholine;

62) 4-(4-(imidazolo)metil)-2-(3-(terc.-butil)-5-(trifluorometil)benziloksi)-3fenil-morfolin;62) 4- (4- (imidazolo) methyl) -2- (3- (tert-butyl) -5- (trifluoromethyl) benzyloxy) -3-phenyl-morpholine;

63) 2-(S)-(3,5-diklorobenziloksi)-3-(S)-fenil-morfolin;63) 2- (S) - (3,5-dichlorobenzyloxy) -3- (S) -phenyl-morpholine;

64) 2-(S)-(3,5-diklorobenziloksi)-4-(3-(5-okso-l,2,4-triazolo)metil)-3-(S)-fenilmorfolin;64) 2- (S) - (3,5-dichlorobenzyloxy) -4- (3- (5-oxo-1,2,4-triazolo) methyl) -3- (S) -phenylmorpholine;

65) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-(metoksikarbonilmetil)-3-(S)-fenilmorfolin;65) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (methoxycarbonylmethyl) -3- (S) -phenylmorpholine;

66) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-(karboksimetil)-3-(S)-fenilmorfolin;66) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (carboxymethyl) -3- (S) -phenylmorpholine;

67) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-((2-ammoetil)ammokarbonilmetil3-(S)-fenil-morfolin;67) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4 - ((2-aminoethyl) aminocarbonylmethyl 3- (S) -phenyl-morpholine;

68) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-((3-aminopropil)aminokarbonilmetil)-3-(S)-fenil-morfolin;68) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4 - ((3-aminopropyl) aminocarbonylmethyl) -3- (S) -phenyl-morpholine;

69) 4-benzil-5-(S),6-(R)-dimetil-3-(S)-fenilmorofolinon in 4-benzil-5-(R),6-(S)dimetil-3-(S)-fenil-morfolinon;69) 4-Benzyl-5- (S), 6- (R) -dimethyl-3- (S) -phenylmorpholinone and 4-benzyl-5- (R), 6- (S) dimethyl-3- (S) -phenyl-morpholinone;

70) 2-(R)-(3,5-bis(trifluorometil)benziloksi)-[5-(S),6-(R) ali 5-(R),6-(S)dimetil]-3-(S)-fenilmorfolinon;70) 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) - [5- (S), 6- (R) or 5- (R), 6- (S) dimethyl] -3- ( S) -phenylmorpholinone;

71) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-[5-(R),6-(S) ali 5-(S),6-(R)dimetil]-3-(S)-fenilmorfolinon;71) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) - [5- (R), 6- (S) or 5- (S), 6- (R) dimethyl] -3- ( S) -phenylmorpholinone;

72) 2-(R)-(3,5-bis(trifluorometil)benziloksi)-4-(3-(l,2,4-triazolo)metil)[5-(S),6-(R) ali 5-(R),6-(S)-dimetil]-3-(S)-fenilmorfolinon;72) 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (3- (1,2,4-triazolo) methyl) [5- (S), 6- (R) or 5 - (R), 6- (S) -dimethyl] -3- (S) -phenylmorpholinone;

73) 2-(R)-(3,5-bis(trifluorometil)benziloksi)-4-(3-(5-okso-l,2,4-triazolo)metil)[5-(S),6-(R) ali 5-(R),6-(S)-dimetil]-3-(S)-fenilmorfolinon;73) 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (3- (5-oxo-1,2,4-triazolo) methyl) [5- (S), 6- ( R) or 5- (R), 6- (S) -dimethyl] -3- (S) -phenylmorpholinone;

74) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-(3-(l,2,4-triazolo)metil)[5-(R),6-(S) ali 5-(S),6-(R)-dimetil]-3-(S)-fenilmorfolinon;74) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (3- (1,2,4-triazolo) methyl) [5- (R), 6- (S) or 5 - (S), 6- (R) -dimethyl] -3- (S) -phenylmorpholinone;

75) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-(3-(5-okso-l,2,4-triazolo)metil)[5-(R),6-(S) ali 5-(S),6-(R)-dimetil]-3-(S)-fenilmorfolinon;75) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (3- (5-oxo-1,2,4-triazolo) methyl) [5- (R), 6- ( S) or 5- (S), 6- (R) -dimethyl] -3- (S) -phenylmorpholinone;

76) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-(2-(l-(4-benzil)piperidino)etil-3(S)-fenilmorfolin;76) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (2- (1- (4-benzyl) piperidino) ethyl-3 (S) -phenylmorpholine;

77) 3-(S)-(4-fluorofenil)-4-benzil-2-morfolinon;77) 3- (S) - (4-fluorophenyl) -4-benzyl-2-morpholinone;

78) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-(4-fluorofenil)-4-benzilmorfo lin;78) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) - (4-fluorophenyl) -4-benzylmorpholine;

79) 2-(S)-(3,5-bis(trifluorometil)benziloksi-3-(S)-(4-fluorofenil)morfolin;79) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy-3- (S) - (4-fluorophenyl) morpholine;

80) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-(4-fluorofenil)-4-(3-(5-oksolH,4H-l,2,4-triazolo)metilmorfolin;80) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) - (4-fluorophenyl) -4- (3- (5-oxolH, 4H-1,2,4- triazolo) methylmorpholine;

81) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-((3-piridil)metilkarbonil)-3-(R)fenilmorfolin;81) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4 - ((3-pyridyl) methylcarbonyl) -3- (R) phenylmorpholine;

82) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-(metoksikarbonilpentil)-3-(R)fenilmorfolin;82) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (methoxycarbonylpentyl) -3- (R) phenylmorpholine;

83) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-(karboksipentil)-3-(R)-fenilmorfolin;83) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (carboxypentyl) -3- (R) -phenylmorpholine;

84) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-(metilaminokarbonilpentil)-6okso-heksil)-3-(R)-fenilmorfolin;84) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (methylaminocarbonylpentyl) -6oxo-hexyl) -3- (R) -phenylmorpholine;

in njihove farmacevtsko sprejemljive soli.and pharmaceutically acceptable salts thereof.

Analiza tahikininskega antagonizmaAnalysis of tachykinin antagonism

Spojine v smislu izuma so uporabne za antagoniziranje tahikininov, še posebno snovi P in nevrokinina A pri zdravljenju gastrointestinalnih motenj, motenj centralnega živčnega sistema, vnetnih bolezni, bolečine ali migrene in astme pri sesalcih, ki takšno zdravljenje potrebujejo. To delovanje lahko ponazorimo z naslednjo analizo.The compounds of the invention are useful for antagonizing tachykinins, in particular substance P and neurokinin A in the treatment of gastrointestinal disorders, central nervous system disorders, inflammatory diseases, pain or migraine and asthma in mammals in need of such treatment. This operation can be illustrated by the following analysis.

A. Receptorsko izražanje v COSA. Receptor expression in COS

Da izrazimo kloniran človeški nevrokinin-1 receptor (NK1R) prehodno v COS, kloniramo cDNA za človeški NK1R v izrazni vektor pCDM9, ki ga izvedemo iz pCDM8 (INVITROGEN) z vstavitvijo ampicilin rezistentnega gena (nukleotid 1973 do 2964 od BLUESCRIPT SK+) v Sac II mesto. Transfekcijo 20 μβ plazmida DNA v 10 milijonov COS celic dosežemo z elektroporacijo v 800 μΐ transfekcijskega pufra (135 mM NaCl, 1,2 mM CaCl2, 1,2 mM MgCl2, 2,4 mM I^HPO^ 0,6 mM KH2PO4, 10 mM glukoze, 10 mM HEPES pH 7,4) pri 260 V in 950 μΡ z uporabo IBI GENEZAPPER (IBI, New Haven, CT). Celice inkubiramo v 10 %-nem zarodkovnemu govejemu serumu, 2 mM glutamina, 100 E/ml penicilin-streptomicina in 90 % DMEM mediju (GIBCO, Grand Island, NY) v 5 % CO2 pri 37 °C tri dni pred izvedbo analize.To express the cloned human neurokinin-1 receptor (NK1R) transiently into COS, we clone the human NK1R cDNA into the expression vector pCDM9 derived from pCDM8 (INVITROGEN) by inserting an ampicillin-resistant gene (nucleotide 1973 to 2964 from BLUESCRIPT SK +) in BLUESCRIPT SK + city. Transfection of 20 μβ DNA plasmid into 10 million COS cells is achieved by electroporation into 800 μΐ of transfection buffer (135 mM NaCl, 1.2 mM CaCl 2 , 1.2 mM MgCl 2 , 2.4 mM I ^ HPO ^ 0.6 mM KH 2 PO 4 , 10 mM glucose, 10 mM HEPES pH 7.4) at 260 V and 950 μΡ using IBI GENEZAPPER (IBI, New Haven, CT). Cells were incubated in 10% fetal bovine serum, 2 mM glutamine, 100 U / ml penicillin-streptomycin and 90% DMEM medium (GIBCO, Grand Island, NY) in 5% CO 2 at 37 ° C for three days before performing the assay.

B. Stabilno izražanje v CHOB. Stable expression in CHO

Da doženemo stabilno celično linijo, ki izraža kloniran človeški NK1R, cDNA subkloniramo v vektor pRcCMV (INVITROGEN). Transfekcijo 20 μg plazmida DNA v CHO celice dosežemo z elektroporacijo v 800 μΐ transfekcijskega pufra dopolnjenega z 0,625 mg/ml Herringove spermijske DNA pri 300 V in 950 μΡ, z uporabo IBI GENEZAPPER (IBI). Transficirane celice inkubiramo v CHO mediju [10 %-ni zarodkovni goveji serum, 100 enot/ml penicilin-streptomicina, 2 mM glutamina, 1/500 hipoksantin-timidina (ATCC), 90 % IMDM medija (JRH BIOSCIENCES, Lenexa, KS), 0.7 mg/ml G418 (GIBCO)j v 5 % CO2 pri 37 °C dokler so kolonije vidne. Vsako kolonijo ločimo in razmnožimo. Celični klon z najvišjim številom človeškega NK1R izberemo za naknadne uporabe, kot je skrining zdravila.To complete a stable cell line expressing cloned human NK1R, the cDNA was subcloned into the pRcCMV vector (INVITROGEN). Transfection of 20 μg of plasmid DNA into CHO cells was achieved by electroporation into 800 μΐ of transfection buffer supplemented with 0.625 mg / ml Herring's sperm DNA at 300 V and 950 μΡ using IBI GENEZAPPER (IBI). The transfected cells were incubated in CHO medium [10% embryonic bovine serum, 100 units / ml penicillin-streptomycin, 2 mM glutamine, 1/500 hypoxanthine-thymidine (ATCC), 90% IMDM medium (JRH BIOSCIENCES, Lenexa, KS). 0.7 mg / ml G418 (GIBCO) in 5% CO 2 at 37 ° C until colonies are visible. Each colony is separated and propagated. The cell clone with the highest number of human NK1R is selected for subsequent use, such as drug screening.

C. Analizni protokol z uporabo COS ali CHOC. Analysis protocol using COS or CHO

Vezivna analiza človeškega NK1R izražena, ali v COS ali CHO celicah, temelji na uporabi 125I-snovi P (125I-S, DU PONT, Boston, MA) kot radioaktivno markiranega liganda, ki konkurira z nemarkirano snovjo P ali katerimkoli drugim ligandom za vezavo na človeški NK1R. Monoplastne celične kulture COS ali CHO disociiramo z ne-encimatsko raztopino (SPECIALTY MEDLA Lavallette, NJ) in ponovno suspendiramo v ustreznem volumnu vezivnega pufra (50 mM Tris pH 7,5, 5 mM MnCl2, 150 mM NaCl, 0,04 mg/ml bacitracina, 0,004 mg/ml levpeptina, 0,2 mg/ml BSA, 0,01 mM fosforamidona), tako da bi 200 μΐ celične suspenzije povzročilo okoli 10.000 cpm specifične 125I-SP vezave (približno 50.000 do 200.000 celic). V vezivni analizi dodamo 200 μΐ celic v cevko, ki vsebuje 20 μΐ 1,5 do 2,5 nM 125I-SP in 20 pel nemarkirane snovi P ali katerekoli druge testne spojine. Cevke inkubiramo pri 4 °C ali pri sobni temperaturi 1 uro z rahlim stresanjem. Vezano radioaktivnost ločimo od nevezane radioaktivnost z GF/C filtrom (BRANDEL, Gaithersburg, MD), ki ga predhodno omočimo z 0,1 %-nim polietileniminom. Filter trikrat speremo s 3 ml pralnega pufra (50 mM Tris pH 7,5, 5 mM MnCl2, 150 mM NaCl) in njegovo radioaktivnost določimo z gama števcem.Binding analysis of human NK1R expressed, whether in COS or CHO cells, is based on the use of 125 I-substance P ( 125 IS, DU PONT, Boston, MA) as a radiolabelled ligand competing with an unmarked substance P or any other ligand for binding to human NK1R. Monoplastic cell cultures of COS or CHO were dissociated with non-enzymatic solution (SPECIALTY MEDLA Lavallette, NJ) and resuspended in appropriate volume of binding buffer (50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl, 0.04 mg / ml bacitracin, 0.004 mg / ml levpeptin, 0.2 mg / ml BSA, 0.01 mM phosphoramidone), so that 200 μΐ of the cell suspension would result in about 10,000 cpm specific 125 I-SP binding (approximately 50,000 to 200,000 cells). In the binding assay, 200 μΐ cells were added to a tube containing 20 μΐ 1.5 to 2.5 nM 125 I-SP and 20 pel of unlabeled substance P or any other test compound. The tubes were incubated at 4 ° C or at room temperature for 1 hour with gentle shaking. The bound radioactivity was separated from the unbound radioactivity with a GF / C filter (BRANDEL, Gaithersburg, MD) prewetted with 0.1% polyethyleneimine. The filter was washed three times with 3 ml of washing buffer (50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl) and its radioactivity was determined by a gamma counter.

Aktivacijo fosfolipaze C z NK1R lahko merimo tudi v CHO celicah, pri čemer izražamo človeški NK1R z določitvijo akumulacije inozitol monofosfata, ki je razgradnji produkt IP3. CHO celice posejemo v 12-vdolbinsko ploščo z 250.000 celicami na vdolbino. Po inkubaciji v CHO mediju 4 dni, celice obremenimo z 0,025 prCi/ml 3H-mioinozitola, pri inkubaciji preko noči. Ekstracelularno radioakktivnost odstranimo s spiranjem s fosfatno napufrano slanico. V vdolbino dodamo LiCl pri končni koncentraciji 0,1 mM z ali brez testne spojine in inkubacijo nadaljujemo 15 min. pri 37 °C. V vdolbino dodamo snov P pri končni koncentraciji 0,3 nM, da aktiviramo človeški NK1R. Po 30 min. inkubacije pri 37 °C, medij odstranimo in dodamo 0,1 N HC1. Vsako vdolbino obdelamo z ultra zvokom pri 4 °C in ekstrahiramo s CHCl3/metanolom (1: 1). Vodno fazo nanesemo na 1 ml Dowex AG 1x8 ionske izmenjevalne kolone. Kolono speremo z 0,1 N mravljične kisline, čemur sledi 0,025 M amonijev format-0,1 N mravljinčna kislina. Inozitol monofosfat eluiramo z 0,2 M amonijevim formatom-0,1 N mravljinčno kislino in kvantificiramo z beta števcem.The activation of phospholipase C by NK1R can also be measured in CHO cells, expressing human NK1R by determining the accumulation of inositol monophosphate, which is a degradation product of IP 3 . CHO cells were seeded into a 12-well plate with 250,000 cells per well. After incubation in CHO medium for 4 days, cells were loaded with 0.025 prCi / ml 3 H-myoinositol upon overnight incubation. Extracellular radioactivity is removed by flushing with phosphate-filled saline. LiCl was added to the well at a final concentration of 0.1 mM with or without the test compound and incubation continued for 15 min. at 37 ° C. Substance P was added to the well at a final concentration of 0.3 nM to activate human NK1R. After 30 min. incubations at 37 ° C, the medium is removed and 0.1 N HCl is added. Each well was treated with ultra-sound at 4 ° C and extracted with CHCl 3 / methanol (1: 1). The aqueous phase is applied to 1 ml of Dowex AG 1x8 ion exchange column. The column was washed with 0.1 N formic acid followed by 0.025 M ammonium formate-0.1 N formic acid. Inositol monophosphate was eluted with 0.2 M ammonium formate-0.1 N formic acid and quantified with a beta counter.

Spojine v smislu predloženega izuma so uporabne pri preprečevanju in zdravljenju širokega izbora kliničnih stanj, za katera je značilna prisotnost prebitka tahikininske aktivnosti, še posebno aktivnosti snovi P.The compounds of the present invention are useful in preventing and treating a wide variety of clinical conditions characterized by the presence of excess tachykinin activity, especially the activity of substance P.

Ta stanja lahko vključujejo motnje centralnega živčnega sistema, kot je anksioznost, depresija, psihoza in shizofrenija; nevrodegenerativne motnje kot je AIDS-u sorodna demenca, senilna demenca Alzheimerjevega tipa, Alzheimerjeva bolezen in Downov sindrom; demielinacijske bolezni, kot je multipla skleroza in amiotropna lateralna skleroza (ALS; Lou Gehrig-ova bolezen) in ostale nevropatološke motnje, kot je periferalna nevropatija, npr. AIDS-u sorodna nevropatija, diabetična nevropatija, kemoterapevtsko-povzročena nevropatija in postherpetične in ostale nevralgije; respiratorne bolezni, kot je kronična bolezen obstrukcije zračnih poti, bronhopnevmonija, bronhospazem in astma; bolezni, za katere je značilno nevrogeno izločanje sluzi, kot je cistična fibroza; vnetne bolezni, kot je vnetna črevesna bolezen, psoriaza, fibrozitis, osteoartritis in revmatoidni artritis; alergije, kot je ekcem in rinitis; motnje hipersenzitivnosti, kot je reakcija na ruj; oftalmične bolezni, kot je konjunkitivitis, spomladanski konjunktivitis in podobno; kožne bolezni, kot je kontaktni dermatitis, atropičen dematitis, urtikarija in ostali ekcematoidni dermatitisi; motnje odvisnosti, kot je alkoholizem; stresu sorodne somatične motnje; refleksna simpatična distrofija, kot je sindrom rame/roke; distimične motnje; negativne imunološke reakcije, kot je zavrnitev transplantiranih tkiv in motnje povezane z imunskim zviševanjem ali zatiranjem, kot je sistemska lupusna eritematoza; gastrointestinalne (Gl) motnje in bolezni Gl trakta, kot so motnje povezane z nevronalno kontrolo drobovja, kot je ulcerativni kolitis, Crohnova bolezen in inkontinenca; bljuvanje, vključno z akutnim, zakasnjenim in prezgodnjim bljuvanjem, npr. povzročenim s kemoterapijo, sevanjem, toksini, nosečnostjo, ravnotežnostno motnjo, gibanjem, kirurškim posegom, migreno in variacijami v medlobanjskem tlaku; motnje funkcije sečnika kot je čezmerna odzivnost potiskalke sečnika; čezmerno razraščanje veznega tkiva in kolagenske bolezni, kot je sklerodermia in eosinofilična fascioliaza; motnje toka krvi povzročene z širjenjem žil in vazospasične bolezni, kot je angina, migrena in Reynaud-ova bolezen; in bolečina ali nocicepcija, npr. ki jo prisodimo ali ki je povezana s katerim koli izmed prej omenjenih stanj, posebno prenosom bolečine in migrene. Torej, lahko te spojine zlahka prilagodimo na terapevtsko uporabo za zdravljenje fizoloških motenj, ki so povezane s prekomerno stimulacijo tahikininskih receptorjev, posebno nevrokinina-1, in kot nevrokinin-1 antagoniste za kontrolo in/ali zdravljenje katerih koli izmed prej omenjenih kliničnih stanj pri sesalcih, vključno ljudjeh.These conditions may include disorders of the central nervous system such as anxiety, depression, psychosis, and schizophrenia; neurodegenerative disorders such as AIDS-related dementia, senile Alzheimer's type dementia, Alzheimer's disease and Down syndrome; demyelinating diseases such as multiple sclerosis and amyotropic lateral sclerosis (ALS; Lou Gehrig's disease) and other neuropathological disorders such as peripheral neuropathy, e.g. AIDS-related neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy and post-herpetic and other neuralgia; respiratory diseases such as chronic airway obstruction, bronchopneumonia, bronchospasm and asthma; diseases characterized by neurogenic mucus secretion, such as cystic fibrosis; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrosis, osteoarthritis and rheumatoid arthritis; allergies such as eczema and rhinitis; disorders of hypersensitivity, such as the reaction to the ruin; ophthalmic diseases such as conjunctivitis, spring conjunctivitis and the like; skin diseases such as contact dermatitis, atropic dematitis, urticaria and other eczemaatoid dermatitis; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy, such as shoulder / arm syndrome; dysthymic disorders; negative immune responses, such as rejection of transplanted tissues and disorders associated with immune elevation or suppression, such as systemic lupus erythematosus; gastrointestinal (Gl) disorders and Gl tract disorders, such as disorders related to neuronal bowel control such as ulcerative colitis, Crohn's disease and incontinence; vomiting, including acute, delayed, and premature vomiting, e.g. caused by chemotherapy, radiation, toxins, pregnancy, balance disorder, movement, surgery, migraine and variations in interplanetary pressure; disorders of the urethra function such as excessive responsiveness of the urethral pusher; excessive growth of connective tissue and collagen disease, such as sclerodermia and eosinophilic fascioliasis; blood flow disorders caused by vascular enlargement and vasospasic diseases such as angina, migraine and Reynaud's disease; and pain or nociception, e.g. which we attribute to or associated with any of the aforementioned conditions, in particular the transmission of pain and migraine. Thus, these compounds can be readily adapted to therapeutic use for the treatment of physiological disorders associated with over-stimulation of tachykinin receptors, especially neurokinin-1, and as neurokinin-1 antagonists for the control and / or treatment of any of the aforementioned mammalian clinical conditions , including people.

Na primer, spojine v smislu predloženega izuma lahko ustrezno uporabimo pri zdravljenju motenj centralnega živčnega sistema, kot so anksioznost, psihoza in shizofrenija; nevrodegenerativnih motenj, kot je senilna demenca Alzheimerjevega tipa, Alzheimerjeva bolezen in Down-ov sindrom; respiratornih bolezni, posebno tis35 tih povezanih s prebitnim izločanjem sluzi, kot je kronična bolezen obstrukcija zračnih poti, bronhopnevmonija, kronični bronhitis, cistična fibroza in astma, in bronhospazem; vnetne bolezni, kot je vnetna črevesna bolezen, osteoartritis in revmatoidni artritis; negativnih imunoloških reakcij, kot je zavrnitev transplantiranih tkiv; gastrointestinalnih (Gl) motenj in bolezni Gl trakta, kot so motnje povezane z nevronsko kontrolo drobovlja, kot je ulcerativni kolitis, Crohnova bolezen in inkontinenca; motenj toka krvi povzročenih s širjenjem žil, in bolečine ali nocicepcije, npr. tiste, ki jo prisodimo, ali ki je povezana s katerim koli izmed prej omenjenih stanj ali prenosom bolečine pri migreni.For example, the compounds of the present invention can be appropriately used in the treatment of central nervous system disorders such as anxiety, psychosis and schizophrenia; neurodegenerative disorders such as senile dementia of Alzheimer's type, Alzheimer's disease and Down syndrome; respiratory diseases, in particular tis35 associated with excessive mucus secretion, such as chronic airway obstruction, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, osteoarthritis and rheumatoid arthritis; negative immune reactions such as rejection of transplanted tissues; gastrointestinal (Gl) disorders and Gl tract disorders, such as disorders related to neural gut control such as ulcerative colitis, Crohn's disease and incontinence; disorders of blood flow caused by vasodilation, and pain or nociception, e.g. one that we attribute to or associated with any of the aforementioned conditions or transmission of migraine pain.

Kot kalcijeva kanalna blokirna sredstva so nekatere izmed spojin v smislu predloženega izuma uporabne pri preprečevanju ali zdravljenju kliničnih stanj na katere ugodno vpliva inhibicija transfer kalcijevih ionov preko membrane plazemske celice. Ta vključujejo bolezni in motnje srca in ožilnega sistema, kot so angina pektoris, miokardialni infarkt, srčna aritmija, srčna hipertrofija, srčni vazospazem, hipertenzija, cerebrovaskularni spazem in ostale ishemične bolezni. Nadalje so lahko te spojine sposobne zniževanja povišanega tlaka v očesu, kadar jih dajemo lokalno na hipertenzivno oko v raztopini v ustreznem očesnem vehiklu. Te spojine delujejo tudi proti odpornosti tumorskih celic na številna zdravila s povečevanjem učinkovitosti kemoterapevtskih sredstev. Poleg tega lahko te spojine delujejo v blokiranju kalcijevih kanalov v možganskih membranah insektov in so lahko tako uporabne kot insekticidi.As calcium channel blockers, some of the compounds of the present invention are useful in preventing or treating clinical conditions that are favorably affected by inhibition of calcium ion transfer across the plasma cell membrane. These include diseases and disorders of the cardiovascular system such as angina, myocardial infarction, cardiac arrhythmia, cardiac hypertrophy, cardiac vasospasm, hypertension, cerebrovascular spasm and other ischemic diseases. Further, these compounds may be capable of reducing the elevated pressure in the eye when administered topically to the hypertensive eye in solution in a suitable eye solvent. These compounds also work against the resistance of tumor cells to many drugs by enhancing the effectiveness of chemotherapeutic agents. In addition, these compounds can act to block calcium channels in insect brain membranes and can be as useful as insecticides.

Spojine v smislu predloženega izuma so posebno uporabne pri zdravljenju bolečine ali nocicepcije in/ali vnetja in motenj povezanih s tem, kot je npr.: nevropatija, kot je diabetična ali periferna nevropatija in kemoterapevtsko povzročena nevropatija; postherpetična in ostale nevralgije; astma, osteoartritis; revmatoidni artritis; in posebno migrena. Spojine v smislu predloženega izuma so tudi posebno uporabne pri zdravljenju bolezni, za katere je značilno nevrogeno izločanje sluzi, posebno cistične fibroze.The compounds of the present invention are particularly useful in the treatment of pain or nociception and / or inflammation and related disorders such as: neuropathy, such as diabetic or peripheral neuropathy and chemotherapy-induced neuropathy; postherpetic and other neuralgia; asthma, osteoarthritis; rheumatoid arthritis; and especially migraine. The compounds of the present invention are also particularly useful in the treatment of diseases characterized by neurogenic mucus secretion, especially cystic fibrosis.

Pri zdravljenju kliničnih stanj navedenih zgoraj, lahko spojine v smislu predloženega izuma uporabimo v sestavkih, kot so tablete, kapsule ali eliksirji za oralno dajanje, supozitozitoriji za reaktalno dajanje, sterilne raztopine ali suspenzije za parenteralno ali intramuskularno dajanje, in podobno.In the treatment of the clinical conditions mentioned above, the compounds of the present invention may be used in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.

Farmacevtske sestavke v smislu izuma lahko uporabimo v obliki farmacevtskega pripravka, npr. v trdni, poltrdni ali tekoči obliki, ki vsebuje eno ali več izmed spojin v smislu izuma, kot aktivno sestavino, v primesi z organskim ali anorganskim nosilcem ali ekscipientom primernim za zunanje, enteralne ali parenteralne uporabe. Aktivno sestavino lahko sestavimo npr. z običajnimi netoksičnimi, farmacevtsko sprejemljivimi nosilci za tablete, pelete, kapsule, svečke, raztopine, emulzije, suspenzije in katero koli drugo obliko primerno za uporabo. Nosilci, ki jih lahko uporabimo so voda, glukoza, laktoza, gumi akacija, želatina, manitol, škrobna pasta, magnezijev trisilikat, smukec, koruzni škrob, keratin, koloidna kremenica, krompirjev škrob, sečnina in ostali nosilci primerni za uporabo v proizvodnji pripravkov, v trdni, poltrdni ali tekoči obliki in poleg lahko uporabimo pomožna, stabilizirna, gostilna in barvalna sredstva in dišave. Aktivno spojino v smislu izuma vključimo v farmacevtski sestavek v količini dovoljšnji, da dosežemo želen učinek na potek ali stanje bolezni.The pharmaceutical compositions of the invention can be used in the form of a pharmaceutical composition, e.g. in solid, semi-solid or liquid form, containing one or more of the compounds of the invention as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral uses. The active ingredient can be assembled e.g. with conventional non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and any other suitable form for use. The carriers that can be used are water, glucose, lactose, acacia gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in the manufacture of preparations, in solid, semi-solid or liquid form, and in addition, auxiliary, stabilizing, inn and dyeing agents and fragrances may be used. The active compound of the invention is incorporated into the pharmaceutical composition in an amount sufficient to achieve the desired effect on the course or condition of the disease.

Za pripravo trdnih sestavkov, kot so tablete, osnovno aktivno sestavino zmešamo s farmacevtskih nosilcem, npr. običajnimi tabletirnimi sestavinami, kot je koruzni škrob, laktoza, saharoza, sorbitol, smukec, stearinska kislina, magnezijev stearat, dikalcijev fosfat ali gumiji, in ostalimi farmacevtskimi razredčili, npr. vodo, da tvorimo trden predformulacijski sestavek, ki vsebuje homogeno zmes spojine v smislu predloženega izuma, ali njeno netoksično farmacevtsko sprejemljivo sol. Kadar omenjamo te predformulacijske sestavke kot homogene, mislimo, da je aktivna sestavina enakomerno dispergirana po vsem sestavku tako, da lahko sestavek zlahka razdelimo v enako učinkovite enotske dozirne oblike, kot so tablete, pilule in kapsule. Ta trden predformulacijski sestavek nato razdelimo v enotske dozirne oblike zgoraj opisanega tipa, ki vsebujejo od 0,1 do okoli 500 mg aktivne sestavine v smislu predloženega izuma. Tablete ali pilule novih sestavkov lahko prevlečemo ali kakor koli drugače sestavimo, da zagotovimo dozirno obliko, ki nudi prednost podaljšanega delovanja. Na primer tableta ali pilula lahko vsebuje notranjo dozirno in zunanjo dozirno komponento, pri čemer je zadnja v obliki ovojnice preko prejšnje. Obe komponenti lahko ločimo z enterično plastjo, ki prepreči razpadanje v želodcu in dovoli notranji komponenti, da gre nedotaknjena v dvanajstnik ali da je zakasnjena v sproščanju. Za takšne enterične plasti ali prevleke lahko uporabimo množico materialov, pri čemer takšni materiali vključujejo številne polimerne kisline in zmesi polimernih kislin s takšnimi materiali kot je šelak, cetilakohol in celulozni acetat.For the preparation of solid compositions such as tablets, the basic active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tabletting ingredients such as cornstarch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums and other pharmaceutical diluents, e.g. water to form a solid preformulation composition comprising a homogeneous mixture of the compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When we refer to these preformulation compositions as homogeneous, we mean that the active ingredient is uniformly dispersed throughout the composition so that the composition can be readily divided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then divided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the new compositions may be coated or otherwise assembled to provide a dosage form that offers the advantage of prolonged action. For example, a tablet or pill may contain an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that prevents decomposition in the stomach and allows the internal component to go intact into the duodenum or be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

Tekoče oblike, v katere lahko vključimo nove sestavke v smislu predloženega izuma, za dajanje oralno ali z injekcijo vključujejo vodno raztopino, ustrezno aromatizirane sirupe, vodne ali oljne suspenzije in aromatizirane emulzije z jedilnimi olji, kot so olje bombažnih semen, sezamovo olje, kokosovo olje ali arašidovo olje, kakor tudi eliksirje in podobne farmacevtske vehikle. Ustrezna disperzijska ali suspendirna sredstva za vodne suspenzije vključujejo sintetične in naravne gumije, kot so tragakant, akacija, alginat, dekstran, natrijeva karboksimetil celuloza, metil celuloza, polivinilpirolidon ali želatina.Liquid forms in which new compositions of the present invention can be incorporated for administration orally or by injection include aqueous solution, appropriately flavored syrups, aqueous or oily suspensions and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical solvents. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone or gelatin.

Sestavki za inhalacijo ali insuflacijo vključujejo raztopine in suspenzije v farmacevtsko sprejemljivih, vodnih ali organskih topilih, ali njihove zmesi, in praške. Tekoči ali trdni sestavki lahko vsebujejo ustrezne farmacevtsko sprejemljive ekscipiente, kot je navedeno zgoraj. Prednosto sestavke dajemo za lokalni ali sistemski učinek po oralni ali nosni respiratorni poti. Sestavke v prednostno sterilnih farmacevtsko sprejemljivih topilih lahko razpršimo z uporabo inertnih plinov. Razpršene raztopine lahko vdihavamo neposredno iz razpršilne naprave ali lahko razpršilno napravo pritrdimo na obrazno masko, šotor ali intermitentni pozitivno tlačni dihalni stroj. Raztopinske, suspenzijske ali praškaste sestavke lahko dajemo prednostno oralno ali nazalno, iz priprav, ki dostavljajo pripravek na primeren način.Inhalation or insufflation compositions include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as indicated above. Preference is given to the composition for topical or systemic effect via the oral or nasal respiratory tract. The compositions in preferably sterile pharmaceutically acceptable solvents can be dispersed using inert gases. Spray solutions can be inhaled directly from the spray device or the spray device can be attached to a face mask, tent or intermittent positive pressure breathing machine. The solution, suspension or powder compositions may be preferably administered orally or nasally, from preparations which deliver the preparation in an appropriate manner.

Za zdravljenje kliničnih stanj in bolezni navedenih zgoraj, lahko spojine v smislu izuma dajemo oralno, lokalno, parenteralno, z inhalacijskim sprejem ali rektalno v dozirnih enotskih pripravkih, ki vsebujejo običajne netoksične farmacevtsko sprejemljive nosilce, adjuvanse in vehikle. Izraz parenteralno, kot ga uporabljamo tukaj, vključuje podkožne injekcije, intravenozne, intramuskularne, intrasternalne injekcijske ali infuzijske tehnike.For the treatment of the clinical conditions and diseases mentioned above, the compounds of the invention may be administered orally, topically, parenterally, by inhalation or rectally in unit dosage formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and solvents. The term parenteral, as used herein, includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.

Za zdravljenje določenih stanj je lahko želeno, da uporabimo spojino v smislu izuma v povezavi z drugim farmakološko aktivnim sredstvom. Na primer za zdravljenje respiratornih bolezni, kot je astma, lahko uporabimo spojino v smislu izuma v povezavi z bronhodilatorjem, kot je /?2-adrenergični receptorski antagonist ali tahikininski antagonist, ki deluje na NK-2 receptorje. Spojino v smislu izuma in bronhodilator lahko dajemo pacientu simultano, zaporedno ali v kombinaciji.For the treatment of certain conditions, it may be desirable to use a compound of the invention in conjunction with another pharmacologically active agent. For example, for the treatment of respiratory diseases such as asthma, a compound of the invention may be used in conjunction with a bronchodilator such as /? 2- adrenergic receptor antagonist or tachykinin antagonist acting on NK-2 receptors. The compound of the invention and the bronchodilator can be administered to the patient simultaneously, sequentially or in combination.

Spojine v smislu izuma lahko dajemo pacientom (živalim in ljudem), ki takšno zdravljenje potrebujejo, v dozah, ki bodo zagotovile optimalno farmacevtsko učinkovitost. Doza bo variirala od pacienta do pacienta, odvisno od narave in resnosti bolezni, pacientove teže, posebnih diet pacienta, hkratne medikacije in ostalih faktorjev, kijih prepoznajo strokovnjaki.The compounds of the invention can be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. The dose will vary from patient to patient, depending on the nature and severity of the disease, the patient's weight, specific patient diets, concomitant medication, and other factors recognized by the skilled artisan.

Pri zdravljenju stanj povezanih s prebitkom tahikininov, bo ustrezen dozirni nivo splošno okoli 0,001 do 50 mg na kg pacientove telesne teže na dan, kar lahko dajemo v posameznih ali večkratnih odmerkih. Prednostno bo dozirni nivo okoli 0,01 do okoli 25 mg/kg na dan; bolj prednostno okoli 0,05 do okoli 10 mg/kg na dan. Na primer, pri zdravljenju stanj, ki vključujejo nevtrotransmisijo občutkov bolečine, je ustrezen dozirni nivo okoli 0,01 do 25 mg/kg na dan, prednostno okoli 0,005 do 10 mg/kg na dan, in posebno okoli 0,005 do 5 mg/kg na dan. Spojine lahko dajemo po režimu 1 do 4 krat na dan, prednostno enkrat ali dvakrat dnevno.In the treatment of conditions associated with excess tachykinins, the appropriate dosage level will generally be about 0.001 to 50 mg per kg of body weight per day, which can be given in single or multiple doses. Preferably, the dosage level will be about 0.01 to about 25 mg / kg per day; more preferably about 0.05 to about 10 mg / kg per day. For example, in the treatment of conditions involving the transmission of pain sensations, the appropriate dosage level is about 0.01 to 25 mg / kg per day, preferably about 0.005 to 10 mg / kg per day, and in particular about 0.005 to 5 mg / kg per day. day. The compounds may be administered by the regimen 1 to 4 times daily, preferably once or twice daily.

V naslednjih shemah in primerih so ponazorjene različne metode za pripravo spojin v smislu predloženega izuma, kjer so R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 in R13 kot je definirano zgoraj.The following schemes and examples illustrate various methods of preparing the compounds of the present invention, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 as defined above.

Okrajšave uporabljene v shemah in primerihAbbreviations used in schemes and cases

Tabela 1Table 1

Reagenti: Reagents: Et3NEt 3 N trietilamin triethylamine Ph3PPh 3 P trifenilfosfin triphenylphosphine TFA TFA trifluoroocetna kislina trifluoroacetic acid NaOEt NaOEt natrijev etoksid sodium ethoxide DCC DCC N,N’-dicikloheksilkarbodiimid N, N′-dicyclohexylcarbodiimide DCU DCU N,N’-dicikloheksilsečnina N, N'-dicyclohexylurea CDI CDI 1,1 ’-karbonildiimidazol 1,1 '-carbonyldiimidazole MCPBA MCPBA m-kloroperbenzojska kislina m-chloroperbenzoic acid DBU DBU l,8-diazabiciklo[5.4.0]undec-7-en 1,8-diazabicyclo [5.4.0] undec-7-ene Cbz-Cl Cbz-Cl benzil kloroformat benzyl chloroformate iPr2NEt ali DIEAiPr 2 NEt or DIEA N,N-diizopropiletilamin N, N-diisopropylethylamine NHS NHS N-hidroksisukcinimid N-hydroxysuccinimide DIB AL DIB AL diizobutilaluminijev hidrid diisobutylaluminum hydride Me9S0.Me 9 S0. dimetil sulfat dimethyl sulfate HOBt HOBt 1-hidroksibenzotriazol hidrat 1-Hydroxybenzotriazole hydrate EDAC EDAC l-etil-3-(3-dimetilaminopropil)karbodiimidhidroklorid 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

Tonila: Tonila: DMF DMF dimetilformamid dimethylformamide THF THF tetrahidrofuran tetrahydrofuran MeOH MeOH metanol methanol EtOH EtOH etanol ethanol AmOH AmOH n-amil alkohol n-amyl alcohol AcOH AcOH ocetna kislina acetic acid MeCN MeCN acetonitril acetonitrile DMSO DMSO dimetilsulfoksid dimethylsulfoxide

Ostali: Other: Ph Ph fenil phenyl Ar Ar aril aryl Me Me metil methyl Et Et etil ethyl iPr iPr izopropil isopropyl Am Am n-amil n-amyl Cbz Cbz karbobenziloksi (benziloksi-karbonil) carbobenzyloxy (benzyloxy-carbonyl) BOC BOC terc.-butoksikarbonil tert.-butoxycarbonyl PTC PTC katalizator faznega prenosa phase transfer catalyst cat. cat. katalitska catalytic FAB-MS FAB-MS hitra atomska bombandirna masna spektrometrija rapid atomic bombardment mass spectrometry rt rt sobna temperatura room temperature

SHEMA 1SCHEME 1

IIIIII

R1-XR 1 -X

K2CO3, iPrOH, ΔK 2 CO 3 , iPrOH, Δ

SHEMA 1 (nad.)SCHEME 1 (cont.)

IVIV

H* toluen ΔH * toluene Δ

SHEMA 2SCHEME 2

VIVI

VII oVII o

1) NaBH^1) NaBH ^

2) TFA2) TFA

VIIIVIII

SHEMA 2 (nad.)SCHEME 2 (cont.)

XIXI

SHEMA 3SCHEME 3

XIIIXIII

SHEMA 3 (nad.)SCHEME 3 (sup.)

NaIO4 ->NAIO 4 ->

HOAc rt (n= 1 ) aliHOAc rt (n = 1) or

60°C (n=2)60 ° C (n = 2)

XVXV

BrNr

R'R '

SHEMA 4SCHEME 4

HO- RHO-R

H*H *

BrNr

R'R '

OR4>OR 4 >

toluen Δtoluene Δ

SHEMA 5SCHEME 5

) PhC HO, OH -►) PhC HO, OH -►

2) NaBH*.2) NaBH *.

FfeOH/H2OFfeOH / H 2 O

BrCHR2CHR3BrBrCHR 2 CHR 3 Br

K2CO3, DMF 100°CK 2 CO 3 , DMF 100 ° C

DIBALHDIBALH

Sli L-SelectrideSimilar to L-Selectride

-78°C-78 ° C

SHEMA 5 (nad.) SCHEME 5 (cont.)

r8 R7 r 8 R 7

NaHNaH

THF <THF <

SHEMA 5 (nad.)SCHEME 5 (cont.)

THF, hfeOHTHF, hfeOH

SHEMA 6SCHEME 6

1) (CF3SO2)2O, CCl4 1) (CF 3 SO 2 ) 2 O, CCl 4

2) filtriraj pod2) filter under

3) koncentrat, razredči v toluenu3) concentrate, diluted in toluene

SHEMA 6 (nad.)SCHEME 6 (cont.)

R'R '

H2, 1 0% Pd/C r3 EtOH, H2OH 2 , 1 0% Pd / C r 3 EtOH, H 2 O

,.dO, .dO

11

R13 R 13

SHEMA 6 (nad.)SCHEME 6 (cont.)

X^^R1 DIEA ->.X ^^ R 1 DIEA ->.

DMF ali CH3CNDMF or CH 3 CN

Δ aliΔ or

R1CHO, NaBH3CN THF, IfeOHR 1 CHO, NaBH 3 CN THF, IfeOH

SHEMA 7SCHEME 7

R 1) pivaloil klorid, n r3n· eter, °°c 2) O'Li+ R 1) pivaloyl chloride, n r 3 n · ether, °° c 2 ) O'Li +

THF, -78°C do 0°CTHF, -78 ° C to 0 ° C

) KHMDS, THF, -78°C) KHMDS, THF, -78 ° C

2) Ar' SO2N3, THF, -78°C2) Ar 'SO 2 N 3 , THF, -78 ° C

3) HOAc3) HOAc

HH

1) LiOH, THF/voda1) LiOH, THF / water

2) H2, Pd/C, HOAc/voda2) H 2 , Pd / C, HOAc / water

Spojine v smislu predloženega izuma, v katerih je X = Y = O lahko pripravimo s splošno potjo, skicirano v shemi 1. Tako lahko ustrezno substituiran a-bromofenilacetaldehid, dimetilacetal I (pripravljen z uporabo postopka Jacobsa v Journal of the American Chemical Society, 1953, 75, 5500) pretvorimo v dibenzil acetal II z mešanjem I in rahlim prebitkom benzil alkohola v prisotnosti kislinskega katalizatorja s hkratno odstranitvijo metanola. Alkilacija substituiranega amino alkohola z benzil bromidom II lahko da N-alkil amino alkohol III; uporaba kiralnega amino alkohola bi imela za posledico tvorbo diastereomerov in te lahko ločimo na tej (ali na kasnejši) stopnji z uporabo standardnih kromatografskih postopkov. N-alkilacija ali N-acilacija III lahko da dialkil- ali acil/alkil-amino alkohol IV, v katerem lahko skupina R1 služi kot zaščitna skupina, ali jo lahko uporabimo kot, ali pretvorimo v substituent v končni ciljni spojini. Ciklizacijo, da dobimo substituiran morfolin V, lahko izvedemo s segrevanjem raztopine IV in s kislinskim katalizatorjem. Diastereomere V, ki se lahko tvorijo, lahko ločimo z uporabo standardnih kromatografskih postopkov. Če je R1 zaščitna skupina, jo lahko odstranimo z uporabo znanih postopkov (Greene, T.W., Wuts, P.G.M. Protective Groups in Organic Synthesis, 2. izd., John Wiley & Sons, Inc., New York, 1991). Če ima priprava I - V za posledico tvorbo enantiomerov, te lahko ločimo z alkilacijo ali acilacijo V (R1 = H) s kiralnim pomagalom, pri čemer ločimo tako nastale diastereomere z uporabo znanih kromatografskih postopkov, in odstranimo kiralno pomagalo, da dobimo enantiomere V. Alternativno lahko diastereomere V ločimo preko frakcionirne kristalizacije iz ustreznega topila diastereomernih soli, ki se tvorijo s V in kiralne organske kisline.Compounds of the present invention in which X = Y = O can be prepared by the general route outlined in Scheme 1. Thus, a suitably substituted α-bromophenylacetaldehyde, dimethylacetal I (prepared using the Jacobs method in the Journal of the American Chemical Society, 1953 , 75, 5500) is converted to dibenzyl acetal II by mixing I and a slight excess of benzyl alcohol in the presence of an acid catalyst while removing methanol. Alkylation of the substituted amino alcohol with benzyl bromide II can give N-alkyl amino alcohol III; the use of chiral amino alcohol would result in the formation of diastereomers and can be separated at this (or at a later stage) using standard chromatographic procedures. N-alkylation or N-acylation III can give dialkyl- or acyl / alkyl-amino alcohol IV, in which the R 1 group can serve as a protecting group, or it can be used as, or converted to a substituent in the final target compound. Cyclization to obtain substituted morpholine V can be carried out by heating solution IV and using an acid catalyst. The diastereomers V that can be formed can be separated using standard chromatographic procedures. If R 1 is a protecting group, it can be removed using known methods (Greene, TW, Wuts, PGM Protective Groups and Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York, 1991). If the preparation of I - V results in the formation of enantiomers, they can be separated by alkylation or acylation of V (R 1 = H) with a chiral auxiliary, separating the resulting diastereomers using known chromatographic procedures, and removing the chiral auxiliary to obtain the enantiomers V Alternatively, the diastereomers of V can be separated via fractionation crystallization from a suitable solvent of the diastereomeric salts formed with V and of chiral organic acids.

Spojine v smislu predloženega izuma, v katerih je X = O in Y = CH2, lahko pripravimo s splošno potjo skicirano v shemi 2. Tako lahko N-metoksi-N-metilamid zaščitenega fenil glicina VI (pripravljenega iz karboksilne kisline preko mešanega anhidrida po postopku Rapoport-a v Journal of Organic Chemistry, 1985, 50, 3972) uporabimo, da aciliramo litijev enolat metil dietilfosfonata, da dobimo ketofosfonat VIL Natrijevo sol VII lahko kondenziramo z ustrezno substituiranim benzaldehidom, da dobimo α,/3-nenasičen keton VIII. Redukcija ketona in odstranitev t-butilkarbamat zaščitne skupine, lahko da amino alkohol IX; diastereomere, ki se lahko tvorijo, lahko ločimo na tej (ali na kasnejši) stopnji z uporabo standardnih kromatografskih tehnik. Williamson-ova eterifikacija IX, pri čemer uporabimo substituiran kloroacetat, čemur sledi segrevanje, ima lahko za posledico tvorbo morfolina X. Redukcijo dvojne vezi in amid karbonila lahko izvedemo na enostaven način, da dobimo substituiran morfolin XI. Če ima priprava VI - XI za posledico tvorbo enantiomerov, te lahko ločimo z alkiliranjem ali aciliranjem XI (R1 = H) s kiralnim pomagalom, pri čemer ločimo tako nastale diastereomere z uporabo znanih kromatografskih postopkov, in odstranimo kiralno pomagalo, da dobimo enantiomere XI. Alternativno lahko diastereomere XI ločimo preko frakcionirne kristalizacije iz ustreznega topila diastereomernih soli, ki se tvorijo s XI in kiralne organske kisline. Če je želeno, da je R1 drugačen od H, lahko morofolinski dušik XI nadalje funkcionaliziramo z uporabo standardnih postopkov za alkilacijo ali acilacijo sekundarnih aminov. Če je želeno, da je R2 drugačen od H, lahko morfolin X pretvorimo v karbinolkarbamat (R1 = RO2C, R2 = OH), intermediat, ki ga lahko alkiliramo in bi upoštevali vaiiracije v R2.The compounds of the present invention wherein X = O and Y = CH 2 can be prepared by the general route sketched in Scheme 2. Thus, N-methoxy-N-methylamide of protected phenyl glycine VI (prepared from carboxylic acid via mixed anhydride according to the Rapoport procedure in Journal of Organic Chemistry, 1985, 50, 3972) is used to acylate lithium enolate methyl diethylphosphonate to give VIL ketophosphonate. Sodium salt VII can be condensed with appropriately substituted benzaldehyde to give α, 3-unsaturated ketone VIII. Reduction of the ketone and removal of the t-butylcarbamate protecting group may give amino alcohol IX; The diastereomers that can be formed can be separated at this (or later) stage using standard chromatographic techniques. Williamson etherification IX, using substituted chloroacetate followed by heating, can result in the formation of morpholine X. The reduction of the double bond and the carbonyl amide can be carried out in a simple manner to give substituted morpholine XI. If the preparation of VI - XI results in the formation of enantiomers, they can be separated by alkylation or acylation of XI (R 1 = H) with a chiral aid, separating the resulting diastereomers using known chromatographic procedures, and removing the chiral aid to obtain the enantiomers of XI . Alternatively, the diastereomers of XI can be separated via fractionation crystallization from a suitable solvent of the diastereomeric salts formed with XI and chiral organic acids. If R 1 is desired to be different from H, morofolin nitrogen XI can be further functionalized using standard procedures for alkylation or acylation of secondary amines. If it is desired that R 2 is other than H, the morpholine X can be converted to carbinolcarbamate (R 1 = RO 2 C, R 2 = OH), an alkylable intermediate to account for the variations in R 2 .

Spojine v smislu predloženega izuma, v katerih je X = S-(O)n (n = 0, 1 2) in Y = 0, lahko pripravimo s splošno potjo skicirano v shemi 3. Tako lahko alkohol IV (pripravljen v shemi 1) pretvorimo v tioacetat XII z uporabo znanih postopkov (Volante, R.P. Tetrahedron Letters, 1981, 22, 3119). Razcepitev estrskega dela, da dobimo tiol XIII, lahko izvedemo z vodno bazo ali reduktivno, odvisno od oviranj, na katere vplivajo ostale prisotne funkcionalne skupine. Kristalizacijo XIII do tiomorfolina XIV lahko naredimo s segrevanjem raztopine XIII in kislinskim katalizizatorjem. Oksidacija XIV, pri čemer uporabimo natrijev metaperjodat v ocetni kislini lahko da sulfoksid ali sulfon XV. Diastereomere XIV ali XV, ki se lahko tvorijo, lahko ločimo z uporabo standardnih kromatografskih postopkov. Če je R1 zaščitna skupina, jo lahko odstranimo z uporabo znanih postopkov (Greene, T.W., Wuts, P.G.M. Protective Groups in Organic Synthesis, 2. izd., John Wiley & Sons, Inc., New York, 1991). Če ima priprava XII - XV za posledico tvorbo enantiomerov, te lahko ločimo z alkiliranjem ali aciliranjem XIV ali XV (R1 = H) s kiralnim pomagalom, pri čemer ločimo tako nastale diastereomere z uporabo znanih kromatografskih postopkov, in odstranimo kiralno pomagalo, da dobimo enantiomere XIV ali XV. Alternativno lahko diastereomere XIV ali XV ločimo preko frakcionirne kristalizacije iz ustreznega topila diastereomernih solih, ki se tvorijo s XIV ali XV in kiralne organske kisline.The compounds of the present invention wherein X = S- (O) n (n = 0, 1 2) and Y = 0 can be prepared by the general route sketched in Scheme 3. Thus, alcohol IV (prepared in Scheme 1) is converted to thioacetate XII using known methods (Volante, RP Tetrahedron Letters, 1981, 22, 3119). The cleavage of the ester moiety to give thiol XIII can be carried out with a water base or reductively, depending on the obstacles affected by the other functional groups present. Crystallization of XIII to thiomorpholine XIV can be done by heating solution XIII and an acid catalyst. Oxidation XIV using sodium metaperiodate in acetic acid may give sulfoxide or sulfone XV. The diastereomers XIV or XV that can be formed can be separated using standard chromatographic procedures. If R 1 is a protecting group, it can be removed using known methods (Greene, TW, Wuts, PGM Protective Groups and Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York, 1991). If the preparation of XII-XV results in the formation of enantiomers, they can be separated by alkylation or acylation of XIV or XV (R 1 = H) with a chiral auxiliary, separating the diastereomers thus formed using known chromatographic procedures, and removing the chiral auxiliary to give enantiomers XIV or XV. Alternatively, the diastereomers of XIV or XV can be separated via fractionation crystallization from a suitable solvent of the diastereomeric salts formed with XIV or XV and chiral organic acids.

Spojine v smislu predloženega izuma, v katerih je X = Y = O, lahko tudi pripravimo po splošni poti, skicirani v shemi 4. Tako lahko ustrezno substituiran a-bromoacetaldehid, dimetil acetal (pripravljen za uporabo postopka Jacobs-a v Journal of the American Chemical Society, 1953, 75, 5500) pretvorimo v acetal z mešanjem in rahlim prebitkom ustreznega alkohola v prisotnosti kislinskega katalizatorja, s hkratno odstranitvijo metanola. Alkilacija substituiranega amino alkohola z bromidom lahko da N-alkil amino alkohol; uporaba kiralnega amino alkohola bi imela za posledico tvorbo diastereomerov in te lahko ločimo na tej (ali kasnejši) stopnji z uporabo standardnih kromatografskih postopkov. N-alkilacija ali N-acilacija lahko da dialkil- ali acil/alkil-amino alkohol, v katerem lahko skupina R1 služi kot zaščitna skupina, ali jo lahko uporabimo ali pretvorimo v substituent v končni ciljni spojini. Ciklizacijo, da dobimo substituiran morfolin, lahko izvedemo s segrevanjem raztopine s kislinskim katalizatorjem. Diastereomere, ki se lahko tvorijo, lahko ločimo z uporabo standardnih kromatografskih postopkov. Če je R1 zaščitna skupina, jo lahko odstranimo z uporabo znanih postopkov (Greene, T.W., Wuts, P.G.M. Protective Groups in Organic Synthesis, 2. izd., John Wiley & Sons, Inc., New York, 1991). Če ima priprava takšnih spojin za posledico tvorbo enantiomerov, lahko te ločimo z alkiliranjem ali aciliranjem končnega produkta (R1 = H) s kiralnim pomagalom, pri čemer ločimo tako nastale diastereomere z uporabo znanih kromatografskih postopkov, in odstranimo kiralno pomagalo, da dobimo želene enantiomere. Alternativno lahko diastereomere ločimo preko frakcionirne kristalizacije iz ustreznega topila diastereomernih soli, ki se tvorijo s spojino kiralne organske kisline.The compounds of the present invention wherein X = Y = O can also be prepared by the general route outlined in Scheme 4. Thus, a suitably substituted α-bromoacetaldehyde, dimethyl acetal (ready for use by the Jacobs process in the Journal of the American The Chemical Society, 1953, 75, 5500) is converted to acetal by stirring and a slight excess of the corresponding alcohol in the presence of an acid catalyst, while removing methanol. Alkylation of the substituted amino alcohol with bromide can give N-alkyl amino alcohol; the use of chiral amino alcohol would result in the formation of diastereomers and can be separated at this (or later) stage using standard chromatographic procedures. N-alkylation or N-acylation can give a dialkyl or acyl / alkyl-amino alcohol in which the R 1 group can serve as a protecting group, or it can be used or converted to a substituent in the final target compound. Cyclization to give substituted morpholine can be carried out by heating the solution with an acid catalyst. The forming diastereomers can be separated using standard chromatographic procedures. If R 1 is a protecting group, it can be removed using known methods (Greene, TW, Wuts, PGM Protective Groups and Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York, 1991). If the preparation of such compounds results in the formation of enantiomers, they can be separated by alkylation or acylation of the final product (R 1 = H) with a chiral aid, separating the resulting diastereomers using known chromatographic methods, and removing the chiral aid to obtain the desired enantiomers. . Alternatively, diastereomers can be separated by fractionation crystallization from a suitable solvent of diastereomeric salts formed with a chiral organic acid compound.

En postopek sintetiziranja enantiomerno čistih substituiranih morfolinov je ponazorjen v shemi 5. Zaščita enantiomerno čistega fenilglicina kot N-benzil derivata, čemur sledi dvojna alkilacija z 1,2-dibromoetanskim derivatom, vodi do morfolinona. Redukcija z aktivinim hidridnim reagentom, kot je diizobutil aluminijev hidrid, litijev aluminijev hidrid, litijev tri(sek.-butil)-borohidrid (L-Selectride®) ali drugimi reducirnimi sredstvi vodi pretežno do 2,3-trans morfolinskih derivatov. Alkilacija alkohola, odstranitev zaščitne skupine na dušiku (npr. s paladijevim hidrogenacijskim katalizatorjem ali 1-kloroetil kloroformatom (Olofson v J. Org. Chem., 1984, 2081 in 2795)) in alkilacija dušika da 2,3-trans spojine.One procedure for synthesizing enantiomerically pure substituted morpholines is illustrated in Scheme 5. Protection of enantiomerically pure phenylglycine as N-benzyl derivative, followed by double alkylation with 1,2-dibromoethane derivative, leads to morpholinone. Reduction with an actinic hydride reagent such as diisobutyl aluminum hydride, lithium aluminum hydride, lithium three (sec-butyl) -borohydride (L-Selectride®) or other reducing agents results in predominantly 2,3-trans morpholine derivatives. Alkylation of alcohol, removal of the protecting group on nitrogen (e.g. with palladium hydrogenation catalyst or 1-chloroethyl chloroformate (Olofson in J. Org. Chem., 1984, 2081 and 2795)) and alkylation of nitrogen yields 2,3-trans compounds.

En postopek za pridobivanje enantiomerno čistih 2,3-cis morfolinov je ponazorjen v shemi 6. V prvem koraku izvedemo tvorbo trifluorometansulfonatnega estra ustreznega benzil alkohola (posebno benzil alkoholov, ki so substituirani z elektronodvzemnimi skupinami, kot so -NO2, -F, -Cl, -Br, -COR, -CF3, itd.) v prisotnosti nereaktivne baze, v inertnem topilu. Uporabimo lahko tudi ostale odhodne skupine, kot je jodid, mezilat, tozilat, p-nitrofenilsulfonat in podobne. Ustrezne baze vključujejo 2,6-di-t-butilpiridin, 2,6-di-t-butil-4-metilpiridin, diizopropiletilamin, kalijev karbonat, natrijev karbonat in podobne. Ustrezna topila vključujejo toluen, heksan, benzen, ogljikov tetraklorid, diklorometan, kloroform, dikloroetan in podobne in njihove zmesi. Nato dodamo filtrirano raztopino triflata k raztopini intermediata, ki nastane, ko morfolin spravimo v stik z aktivnim hidridnim reagentom, kot je diizobutil aluminijev hidrid, litijev aluminijev hidrid ali litijev ti(sek.-butil)borohidrid (L-Selectride®) pri nizki temperaturi, prednostno od -78 °C do -20 °C. Po nekaj urah pri nizki temperaturi, obdelava in prečiščenje zagotovi predominantno 2,3-cis substituirane produkte, ki jih lahko prevedemo v končne spojine, kot je prikazano v shemi 6.One process for the production of enantiomerically pure 2,3-cis morpholines is illustrated in Scheme 6. In the first step, the formation of the trifluoromethanesulfonate ester of the corresponding benzyl alcohol (in particular benzyl alcohols which are substituted by electron withdrawing groups such as -NO 2 , -F, - Cl, -Br, -COR, -CF 3 , etc.) in the presence of a non-reactive base, in an inert solvent. Other leaving groups such as iodide, mesylate, tosylate, p-nitrophenylsulfonate and the like can also be used. Suitable bases include 2,6-di-t-butylpyridine, 2,6-di-t-butyl-4-methylpyridine, diisopropylethylamine, potassium carbonate, sodium carbonate and the like. Suitable solvents include toluene, hexane, benzene, carbon tetrachloride, dichloromethane, chloroform, dichloroethane and the like and mixtures thereof. Then, a filtered triflate solution is added to the intermediate solution formed when the morpholine is contacted with an active hydride reagent such as diisobutyl aluminum hydride, lithium aluminum hydride or lithium ti (sec-butyl) borohydride (L-Selectride®) at low temperature , preferably from -78 ° C to -20 ° C. After a few hours at low temperature, treatment and purification provide predominantly 2,3-cis substituted products that can be converted to the final compounds as shown in Scheme 6.

Enantiomerno čiste fenil glicine substituirane na fenilnem obroču lahko pripravimo s postopkom, prikazanim v shemi 7 (D.A. Evans, et al, J. Am. Chem. Soc., 1990, 112, 4011).The enantiomerically pure phenyl glycines substituted on the phenyl ring can be prepared by the procedure shown in Scheme 7 (D.A. Evans, et al, J. Am. Chem. Soc., 1990, 112, 4011).

Postopke za pripravo dušikovih alkilacijskih sredstev RJCH2X, uporabljenih v shemi 5 in shemi 6, temeljijo na znanih literaturnih postopkih (za R1 = 3-(l,2,4-triazolil) ali 5-(l,2,4-triazol-3-on)-il in X = Cl, glej Yanagisawa, I.; Hirata, X.; Ishii, X. Journal of Medicinal Chemistry, 1984, 27, 849; za R1 = 4-((2H)-imidazol-2-on)-il ali 5-(4etoksikarbonil-(2H)-imidazol-2-on)-il in X = Br, glej Ducschinsky, R., Dolan, L.A. Journal of the American Chemical Society, 1948, 70, 657).The procedures for the preparation of the nitrogen alkylating agents R J CH 2 X used in Schemes 5 and 6 are based on known literature procedures (for R 1 = 3- (1,2,4-triazolyl) or 5- (1,2,4 -triazol-3-one) -yl and X = Cl, see Yanagisawa, I.; Hirata, X .; Ishii, X. Journal of Medicinal Chemistry, 1984, 27, 849; for R 1 = 4 - ((2H) -imidazol-2-one) -yl or 5- (4ethoxycarbonyl- (2H) -imidazol-2-one) -yl and X = Br, see Ducschinsky, R., Dolan, LA Journal of the American Chemical Society, 1948; 70, 657).

Spojine v smislu izuma s formulo I, ki jih pridobimo po reakcijah, kot je razloženo zgoraj, lahko izoliramo in prečistimo na običajen način, npr. z ekstrakcijo, obarjanjem, frakcionirno kristalizacijo, prekristalizacijo, kromatografijo in podobno.The compounds of the invention of the formula I obtained by the reactions as explained above can be isolated and purified in the usual way, e.g. by extraction, precipitation, fractionation crystallization, recrystallization, chromatography and the like.

Spojine v smislu predloženega izuma lahko tvorijo soli z različnimi anorganskimi in organskimi kislinami in bazami, in takšne soli so tudi znotraj obsega predloženega izuma. Primeri takšnih kislinskih adicijskih soli vključujejo acetat, adipat, benzoat, benzensulfonat, bisulfat, butirat, citrat, kamforat, camforsulfonat, etansulfonat, fumarat, hemisulfat, heptanoat, heksanoat, hidroklorid, hidrobromid, hidrojodid, metansulfonat, laktat, maleat, metansulfonat, 2-naftalensulfonat, oksalat, pamoat, persulfat, pikrat, pivalat, propionat, sukcinat, tartrat, tozilat in undekanoat. Bazične soli vključujejo amonijeve soli, soli alkalijskih kovin, kot so natrijeve, litijeve in kalijeve soli, soli zemljo alkalijskih kovin, kot so kalcijeve in magnezijeve soli, soli z organskimi bazami, kot so dicikloheksilaminske soli, N-metil-D-glukamin, in soli z amino kislinami, kot so arginin, lizin in tako naprej. Tudi bazični dušik-vsebujoče skupine lahko kvarterniziramo s takšnimi sredstvi kot'so: nižji alkil halidi, kot je metil, etil, propil in butil klorid, bromidi in jodidi; dialkil sulfati kot dimetil, dietil, dibutil; diamil sulfati; halidi z dolgimi verigami, kot so decil, lavril, miristil in stearil kloridi, bromidi in jodidi; aralkil halidi kot benzil bromid in drugi. Netoksične fiziološko sprejemljive soli so prednostne, čeprav so druge soli tudi uporabne, kot je v izoliranju ali čiščenju produkta.The compounds of the present invention may form salts with various inorganic and organic acids and bases, and such salts are also within the scope of the present invention. Examples of such acid addition salts include acetate, adipate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, ethanesulfonate, fumarate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, methanesulfonate, lactanate, methanesulfonate, lactate naphthalenesulfonate, oxalate, pamoate, persulfate, picrate, pivalate, propionate, succinate, tartrate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, organic base salts such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine and so on. Also, the basic nitrogen-containing groups can be quaternized with such agents as: lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl bromide and others. Non-toxic physiologically acceptable salts are preferred, although other salts are also useful, such as in isolating or purifying a product.

Soli lahko tvorimo na običajen način, kot s presnovo proste bazične oblike produkta z enim ali večimi ekvivalenti ustrezne kisline v topilu ali mediju, v katerem je sol netopna, ali v topilu, kot je voda, ki ga odstranimo v vakuumu ali z zamrznitvenim sušenjem ali z zamenjavo anionov obstoječe soli za drug anion na ustrezni ion izmenjevalni smoli.Salts can be formed in the usual way, such as by metabolizing the free basic form of the product with one or more equivalents of the corresponding acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or freeze-drying, or by replacing the anions of the existing salt with another anion on the corresponding ion exchange resin.

Čeprav so reakcijske sheme, opisane tu notri, logično splošne, bodo strokovnjaki na področju organske sinteze razumeli, da lahko ena ali več prisotnih funkcionalnih skupin v dani spojini s formulo I nadomesti molekulo, ki je nekompatibilna z določeno sintezno sekvenco.Although the reaction schemes described herein are logically general, those skilled in the art of organic synthesis will understand that one or more of the functional groups present in a given compound of formula I can replace a molecule that is incompatible with a particular synthesis sequence.

V takšnem primeru lahko uporabimo alternativno pot, spremenjeno zaporedje korakov ali strategijo zaščite ali odstranitve zaščite. V vseh primerih moramo izbrati določene reakcijske pogoje, ki vključujejo reagente, topilo, temperaturo in čas tako, da so konsistentni za naravo funkcionalnosti, kije prisotna v molekuli.In such a case, an alternative route, a modified sequence of steps, or a security or removal strategy may be used. In all cases, certain reaction conditions, which include reagents, solvent, temperature, and time, must be chosen to be consistent with the nature of the functionality present in the molecule.

Naslednji primeri so podani za ilustrativni namen predloženega izuma in jih ne gre razlagati pod omejitve obsega ali duha predloženega izuma.The following examples are given for illustrative purposes of the present invention and should not be construed as being limited by the scope or spirit of the present invention.

PRIMER 1 (+/-)-of-bromo-fenilacetaldehid, 3,5-bis(trifluorometil)benzil acetalEXAMPLE 1 (+/-) - Of-bromo-phenylacetaldehyde, 3,5-bis (trifluoromethyl) benzyl acetal

Raztopino 2,50 g (10,2 mmol) α-bromo-fenilacetaldehida, dimetil acetala, 8,00 g (32,8 mmol) 3,5-bis(trifluorometil)benzil alkohola in 0,50 g (2,6 mmol monohidrata p-toluensulfonske kisline v 10 ml toluena mešamo 3 dni pod vakuumom (4,66 kPa) pri sobni temperaturi. Reakcijsko zmes porazdelimo med 100 ml etra in 50 ml nasičene vodne raztopine natrijevega bikarbonata in plasti se ločijo. Organsko plast speremo s 25 ml nasičene vodne raztopine natrijevega klorida, posušimo preko magnezijevega sulfata in koncentriramo v vakuumu. Flash kromatografija na 200 g silikagela, pri čemer uporabimo 9 : 1 v/v heksan/metilen klorid kot eluent, da 5,41 g (81 %) naslovne spojine kot trdne snovi, tal. 79 do 82 °C:A solution of 2.50 g (10.2 mmol) of α-bromo-phenylacetaldehyde, dimethyl acetal, 8.00 g (32.8 mmol) of 3,5-bis (trifluoromethyl) benzyl alcohol and 0.50 g (2.6 mmol) The p-toluenesulfonic acid monohydrate in 10 ml of toluene was stirred for 3 days under vacuum (4.66 kPa) at room temperature The reaction mixture was partitioned between 100 ml of ether and 50 ml of saturated aqueous sodium bicarbonate solution and the layers were separated. of saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo Flash chromatography on 200 g silica gel using 9: 1 v / v hexane / methylene chloride as eluent to give 5.41 g (81%) of the title compound as solids, mp 79 to 82 ° C:

*H NMR 4,47 in 4,62 (AB q, 2 H, J = 12,5), 4,78 - 4,93 (2H), 5,09 in 5,21 (AB q, 2 H, J = 7,7), 7,31 - 7,44 (m, 7 H), 7,70 (jasen s, 1 H), 7,82 (jasen s, 1 H), 7,84 (jasen s, 2 H);* H NMR 4.47 and 4.62 (AB q, 2 H, J = 12.5), 4.78 - 4.93 (2H), 5.09 and 5.21 (AB q, 2 H, J = 7.7), 7.31 - 7.44 (m, 7 H), 7.70 (clear s, 1 H), 7.82 (clear s, 1 H), 7.84 (clear s, 2 H);

IR (tanek film) 1363,1278,1174,1130, 704, 682.IR (thin film) 1363,1278,1174,1130, 704, 682.

Analiza za C26H17BrF12O2:Analysis for C 26 H 17 BrF 12 O 2 :

izrač.: C 46,76; H 2,23; Br 11,64; F 33,70;Calc'd: C, 46.76; H, 2.23; Br 11.64; F 33.70;

ugot.: C 46,65; H 2,56; Br 11,94; F 34,06.Found: C, 46.65; H, 2.56; Br 11.94; F 34.06.

PRIMER 2 (+/-)-N-(2-hidroksietil)-fenilglicinal, 3,5-bis-(trifluorometil)benzil acetalEXAMPLE 2 (+/-) - N- (2-hydroxyethyl) -phenylglycine, 3,5-bis- (trifluoromethyl) benzyl acetal

Raztopino 1,50 g (2,2 mmol) (+/-)-a-bromo-fenilacetaldehida, 3,5-bis(trifluorometil)-benzil acetala (primer 1), 100 mg (0,67 mmol) natrijevega jodida in 3 ml etanolamina v 6 ml izopropanola segrevamo 20 h pri refluksu. Raztopino ohladimo in koncentriramo na —25 % prvotnega volumna v vakuumu. Koncentrirano raztopino porazdelimo med 50 ml etra in 20 ml 2 N vodne raztopine natrijevega hidroksida in plasti se ločijo. Organsko plast speremo z 20 ml nasičene vodne raztopine natrijevega klorida, posušimo preko magnezijevega sulfata in koncentriramo v vakuumu. Flasch kromatografija na 50 g silikagela, pri čemer uporabimo 65 : 35 v/v eter/heksan kot eluent da 1,18 g (83 %) naslovne spojine kot olje:A solution of 1.50 g (2.2 mmol) (+/-) -? - bromo-phenylacetaldehyde, 3,5-bis (trifluoromethyl) -benzyl acetal (example 1), 100 mg (0.67 mmol) of sodium iodide and 3 ml of ethanolamine in 6 ml of isopropanol are refluxed for 20 h. The solution was cooled and concentrated to -25% of the original volume in vacuo. The concentrated solution was partitioned between 50 ml of ether and 20 ml of 2 N aqueous sodium hydroxide solution and the layers separated. The organic layer was washed with 20 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Flasch chromatography on 50 g of silica gel using 65: 35 v / v ether / hexane as eluent to give 1.18 g (83%) of the title compound as an oil:

Ή NMR 2,66 (širok s, 2 H), 2,61 in 2,68 (ddAb q, 2H, JAB = 12,4, J261 = 6,8, 6,2, J26g = 6,2, 6,2), 3,57 in 3,66 (ddAB q, 2 H, JAB = 10,8, J3>57 = 6,2, 6,2)’ J366 = 6,8, 6,2), 4,02 (d, 1 H, J = 7,0), 4,37 in 4,64 (AB q, 2 H, J = 12,5), 4,80 in 4,87 (AB q, 2 H, J = 12,8), 4,87 (d, 1 H, J = 7,0), 7,31 - 7,40 (7 H), 7,73 Gašen s, 1 H), 7,81 Qasen s, 3 H);Ή NMR 2.66 (broad s, 2 H), 2.61 and 2.68 (ddAb q, 2H, J AB = 12.4, J 261 = 6.8, 6.2, J 26g = 6.2 , 6.2), 3.57 and 3.66 (ddAB q, 2 H, J AB = 10.8, J 3> 57 = 6.2, 6.2) 'J 366 = 6.8, 6. 2), 4.02 (d, 1 H, J = 7.0), 4.37 and 4.64 (AB q, 2 H, J = 12.5), 4.80 and 4.87 (AB q , 2 H, J = 12.8), 4.87 (d, 1 H, J = 7.0), 7.31 - 7.40 (7 H), 7.73 Quenched with, 1 H), 7 , 81 Qasen s, 3 H);

IR (čist) 3342,1456,1373,1278,1173,1128, 704, 682;IR (pure) 3342,1456,1373,1278,1173,1128, 704, 682;

FAB-MS 650(M+l)+.FAB-MS 650 (M + 1) + .

Analiza za C^H^F^NO^ izrač.: C 51,78; H 3,57; N 2,16; F 35,11;Analysis for C 25 H 28 F 3 NO 4 Calc: C 51.78; H, 3.57; N, 2.16; F 35.11;

ugot.: C 51,80; H 3,67; N 2,10; F 35,41.Found: C, 51.80; H, 3.67; N, 2.10; F 35.41.

PRIMER 3 (+/-)-N-(2-hidroksietilj-N-(prop-2-enil)-fenilglicinal, 3,5-bis(trifluorometil)benzil acetalEXAMPLE 3 (+/-) - N- (2-hydroxyethyl-N- (prop-2-enyl) -phenylglycine, 3,5-bis (trifluoromethyl) benzyl acetal

Zmes 1,45 g (2,2 mmol) (+/-)-N-(2-hidroksietil)-fenilglicina, 3,5-bis-(trifluorometil)benzil acetala (primer 2), 1,0 g (7,2 mmol) kalijevega karbonata, 3,0 ml (35,0 mmol) alil bromida in 15 ml etanola mešamo 20 h pri 60 °C. Zmes ohladimo, porazdelimo med 100 ml etra in 25 ml vode in plasti ločimo. Organsko plast posušimo preko magnezijevega sulfata. Vodno plast ekstrahiramo s 100 ml etra; etrski ekstrakt posušimo in združimo s prvotno organsko plastjo. Združene organske plasti koncentriramo v vakuumu. Flasch kromatografija na 50 g silikagela, pri čemer uporabimo 4 : 1 v/v heksan/eter kot eluent da 1,36 g (88 %) naslovne spojine kot olje:A mixture of 1.45 g (2.2 mmol) (+/-) - N- (2-hydroxyethyl) -phenylglycine, 3,5-bis- (trifluoromethyl) benzyl acetal (example 2), 1.0 g (7, 2 mmol) of potassium carbonate, 3.0 ml (35.0 mmol) of allyl bromide and 15 ml of ethanol were stirred for 20 h at 60 ° C. The mixture was cooled, partitioned between 100 ml of ether and 25 ml of water and the layers separated. The organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 100 ml of ether; The ether extract is dried and combined with the original organic layer. The combined organic layers were concentrated in vacuo. Flasch chromatography on 50 g of silica gel using 4: 1 v / v hexane / ether as eluant to give 1.36 g (88%) of the title compound as an oil:

Ή NMR 2,40 (dt, 1 H, J = 13,2, 2,8), 2,93 - 3,08 (3 H), 3,30 (ddt, 1 H, J = 12,0, 2,8, 1,6), 3,54 (širok m, 2 H), 3,65 (dt, 1 H, J = 10,0, 2,8), 4,23 (d, 1 H, J = 8,4), 4,52 in 4,58 (AB Q, 2 H, J = 12,4), 4,85 in 4,95 (AB q, 2 H, J = 12,4), 5,25 (d, 1 H, J = 9,6), 5,28 (d, 1 H, J = 16,4), 5,39 (d, 1 H, J = 8,4), 5,81 (m, IH), 7,24 - 7,40 (7 H), 7,68 (s, IH), 7,83 (s, IH), 7,86 (s, 2 H);Ή NMR 2.40 (dt, 1 H, J = 13.2, 2.8), 2.93 - 3.08 (3 H), 3.30 (ddt, 1 H, J = 12.0, 2 , 8, 1.6), 3.54 (broad m, 2 H), 3.65 (dt, 1 H, J = 10.0, 2.8), 4.23 (d, 1 H, J = 8.4), 4.52 and 4.58 (AB Q, 2 H, J = 12.4), 4.85 and 4.95 (AB q, 2 H, J = 12.4), 5.25 (d, 1 H, J = 9.6), 5.28 (d, 1 H, J = 16.4), 5.39 (d, 1 H, J = 8.4), 5.81 (m , 1H), 7.24 - 7.40 (7H), 7.68 (s, 1H), 7.83 (s, 1H), 7.86 (s, 2H);

IR (čist) 345,1362,1278,1174,1132,1056, 759, 705, 682;IR (pure) 345,1362,1278,1174,1132,1056, 759, 705, 682;

FAB-MS 690(M+l)+.FAB-MS 690 (M + 1) + .

Analiza za C31H2?F12NO3:Analysis for C 31 H 2? F 12 NO 3 :

izrač.: C 53,99; H 3,95; N 2,03; F 33,07;Calc'd: C, 53.99; H, 3.95; N, 2.03; F, 33.07;

ugot.: C 54,11; H 4,08; N 1,78; F 32,75.found: C 54.11; H, 4.08; N, 1.78; F, 32.75.

PRIMER 4 (+/-)-2-(3,5-bis(trifluorometil)benziloksi)-3-fenilmorfolinEXAMPLE 4 (+/-) - 2- (3,5-bis (trifluoromethyl) benzyloxy) -3-phenylmorpholine

Korak A: Raztopino 850 mg (1,2 mmol) (+/-)-N-(2-hidroksietil)-N-(prop-2-enil)fenil-glicinala, 3,5-bis(trifluorometil)benzil acetala (primer 3) in 700 mg (3,7 mmol) monohidrata p-toluensulfonske kisline v 15 ml toluena segrevamo 1,5 h pri refluksu. Reakcijsko zmes ohladimo in porazdelimo med 100 ml etra in 25 ml nasičene vodne raztopine natrijevega bikarbonata. Plasti ločimo; organsko plast speremo s 25 ml nasičene vodne raztopine natrijevega klorida, posušimo preko magnezijevega sulfata in koncentriramo v vakuumu. Flash kromatografija na 30 g silikagela, pri čemer uporabimo 50 :1 v/v heksan/eter kot eluent, da 426 mg (78 %) N-alil morfolinov, ki jih uporabimo v naslednjem koraku brez nadaljnjega čiščenja.Step A: A solution of 850 mg (1.2 mmol) (+/-) - N- (2-hydroxyethyl) -N- (prop-2-enyl) phenyl-glycinal, 3,5-bis (trifluoromethyl) benzyl acetal ( Example 3) and 700 mg (3.7 mmol) of p-toluenesulfonic acid monohydrate in 15 ml of toluene was heated at reflux for 1.5 h. The reaction mixture was cooled and partitioned between 100 ml of ether and 25 ml of saturated aqueous sodium bicarbonate solution. The layers are separated; The organic layer was washed with 25 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 30 g of silica gel using 50: 1 v / v hexane / ether as eluant to give 426 mg (78%) of N-allyl morpholines used in the next step without further purification.

Korak B: 50 ml bučko z dvema vratoma, opremljeno z zamaškom in destilacijsko apraturo s kratko potjo, napolnimo z raztopino N-alil morfolinov (primer 4, korak A) (540 mg, 1,2 mmol)) in 80 mg (0,09 mmol) tris(trifenilfosfin)rodijevega klorida (Wilkinson-ov katalizator) v 25 ml 4 : 1 v/v acetonitrila/vode. Reakcijsko zmes segrevamo do vrenja in topilo pustimo, da destilira iz reakcijske zmesi. Volumen reakcijske zmesi vzdržujemo med 10 in 20 ml z dodajanjem topila preko zamašenega vhoda. Po 1 h in 4 h reakcijsko zmes obdelamo z dodatnimi 80 mg deli Wilkinsonovega katalizatorja. Po 6 h reakcijsko zmes ohladimo in porazdelimo med 75 ml etra in 50 ml vode. Plasti ločimo in organsko plast posušimo preko magnezijevega sulfata. Vodno plast ekstrahiramo s 75 ml etra; ekstrakt posušimo in združimo s prvotno organsko plastjo. Združene organske plasti koncentriramo v vakuumu. Flash kromatografija na 35 g silikagela, pri čemer uporabimo 1 : 1 v/v eter/heksan kot eluent, da 200 mg trans-izomera in 130 mg zmesi cis- in trans-izomerov (68 % celokupno). Kromatografija zmesi na 8 g silikagela, pri čemer uporabimo 4 : 1 v/v heksan/eter kot eluent, da 64 mg cis- V in 57 mg zmes cis- in trans-izomerov naslovne spojine.Step B: Fill a 50 ml two-necked flask equipped with a stopper and short-range distillation apparatus filled with a solution of N-allyl morpholines (Example 4, Step A) (540 mg, 1.2 mmol)) and 80 mg (0, 09 mmol) of tris (triphenylphosphine) rhodium chloride (Wilkinson catalyst) in 25 ml of 4: 1 v / v acetonitrile / water. The reaction mixture is heated to boiling and the solvent is allowed to distill from the reaction mixture. The volume of the reaction mixture was maintained between 10 and 20 ml by adding solvent via a clogged inlet. After 1 h and 4 h, the reaction mixture was treated with an additional 80 mg portions of Wilkinson catalyst. After 6 h, the reaction mixture was cooled and partitioned between 75 ml of ether and 50 ml of water. The layers were separated and the organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 75 ml of ether; the extract is dried and combined with the original organic layer. The combined organic layers were concentrated in vacuo. Flash chromatography on 35 g of silica gel using 1: 1 v / v ether / hexane as eluent to give 200 mg of trans-isomer and 130 mg of a mixture of cis- and trans-isomers (68% overall). Chromatography of the mixture on 8 g of silica gel using 4: 1 v / v hexane / ether as eluant to give 64 mg of cis-V and 57 mg of a mixture of cis- and trans-isomers of the title compound.

Za trans-V: Ή NMR 2,03 (širok s, 1 H), 2,94 (ddd, 1 H, J = 11,0, 2,5, 2,5), 3,08 (dt, 1 H, J = 11,0, 3,2), 3,71 (d, 1 H, J = 7,0), 3,83 (dt, 1 H, J = 11,2, 2,8), 4,05 (ddd, 1 H, J = 11,2, 3,2, 3,2), 4,43 (d, 1 H, J = 7,0), 4,53 in 4,88 (AB q, 2 H, J = 13,3), 7,26 - 7,45 (7H), 7.70(s, IH);For trans-V: Ή NMR 2.03 (broad s, 1 H), 2.94 (ddd, 1 H, J = 11.0, 2.5, 2.5), 3.08 (dt, 1 H) , J = 11.0, 3.2), 3.71 (d, 1 H, J = 7.0), 3.83 (dt, 1 H, J = 11.2, 2.8), 4, 05 (ddd, 1 H, J = 11.2, 3.2, 3.2), 4.43 (d, 1 H, J = 7.0), 4.53 and 4.88 (AB q, 2 H, J = 13.3), 7.26-7.45 (7H), 7.70 (s, 1H);

IR (čist) 3333, 2859,1456,1374,1278,1173,1131,1082, 757, 702, 682; FAB-MS 406(M+l)+.IR (pure) 3333, 2859,1456,1374,1278,1173,1131,1082, 757, 702, 682; FAB-MS 406 (M + 1) + .

Analiza za C19H1?F6NO2:Analysis for C 19 H 1? F 6 NO 2 :

izrač.: C 56,30; H 4,23; N 3,46; F 28,12;Calc'd: C, 56.30; H, 4.23; N, 3.46; F 28.12;

ugot.: C 56,39; H 4,28; N 3,36; F 28,32.found: C, 56.39; H, 4.28; N, 3.36; F 28.32.

Za cis-V: Ή NMR 2,10 (širok s, 1 H), 3,13 (dd, 1 H, J = 12,4, 3,0), 3,26 (dt, 1 H, J = 12,4, 3,6), 3,65 (dd, 1 H, J = 11,6, 3,6), 4,07 (dt, I H, J = 11,6, 3,0), 4,14 (d, 1 H, J = 2,4), 4,52 in 4,82 (AB q, 2 H, J = 13,6), 4,76 (d, 1 H, J = 2,4), 7,30 - 7,42 (6 H), 7,70 (s, IH).For cis-V: Ή NMR 2.10 (broad s, 1 H), 3.13 (dd, 1 H, J = 12.4, 3.0), 3.26 (dt, 1 H, J = 12 , 4, 3.6), 3.65 (dd, 1H, J = 11.6, 3.6), 4.07 (dt, 1H, J = 11.6, 3.0), 4.14 (d, 1 H, J = 2.4), 4.52 and 4.82 (AB q, 2 H, J = 13.6), 4.76 (d, 1 H, J = 2.4), 7.30 - 7.42 (6H), 7.70 (s, 1H).

FAB-MS 406(M+l)1.FAB-MS 406 (M + 1) 1 .

PRIMER 5 (+/-)-2-(3,5-bis(trifluorometil)benziloksi)-3-fenil-4-metilkarboks-amido morfolinEXAMPLE 5 (+/-) - 2- (3,5-bis (trifluoromethyl) benzyloxy) -3-phenyl-4-methylcarboxamido morpholine

Raztopino 105 mg (0,26 mmol) trans-izomera (+/-)-2-(3,5-bis(trifluorometil)benziloksi)-3-fenil-morfolina (primer 4) in 0,09 ml (0,50 mmol) N,Ndiizopropiletilamina v 3 ml acetonitrila obdelamo z 90 mg (0,50 mmol) jodoacetamida in nastalo raztopino mešamo 16 h pri sobni temperaturi. Raztopino koncentriramo v vakuumu in ostanek porazdelimo med 20 ml etil acetata in 10 ml 0,5 N vodne raztopine kalijevega hidrogen sulfata. Plasti ločimo; organsko plast speremo z 10 ml 5 % vodne raztopine natrijevega tiosulfata, 10 ml nasičene vodne raztopine natrijevega bikarbonata, 10 ml nasičene vodne raztopine natrijevega klorida, posušimo preko magnezijevega sulfata in koncentriramo v vakuumu. Flash kromatografija na 5 g silikagela, pri čemer uporabimo 2 : 1 v/v etil acetat/heksan kot eluent, da 99 mg (82 %) trans-izomera naslovne spojine kot olje:A solution of 105 mg (0.26 mmol) of the (+/-) - 2- (3,5-bis (trifluoromethyl) benzyloxy) -3-phenyl-morpholine trans isomer (Example 4) and 0.09 ml (0.50) mmol) of N, Ndiisopropylethylamine in 3 ml of acetonitrile was treated with 90 mg (0.50 mmol) of iodoacetamide and the resulting solution was stirred for 16 h at room temperature. The solution was concentrated in vacuo and the residue partitioned between 20 ml of ethyl acetate and 10 ml of 0.5 N aqueous potassium hydrogen sulphate solution. The layers are separated; The organic layer was washed with 10 ml of 5% aqueous sodium thiosulphate solution, 10 ml of saturated aqueous sodium bicarbonate solution, 10 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 5 g of silica gel using 2: 1 v / v ethyl acetate / hexane as eluent to give 99 mg (82%) of the trans isomer of the title compound as an oil:

Ή NMR 2,56 (dt, 1 H, J = 3,2,11,6), 2,67 in 3,16 (AB q, 2H, J = 16,4), 2,96 (dt, 1 H, J = 12,0, 1,6), 3,30 (d, 1 H, J = 7,0), 3,86 (dt, 1 H, J = 3,2, 12,0), 4,08 (ddt, 1 H, J = 11,6, 3,2,1,6), 4,48 in 4,84 (AB q, 2 H, J = 13,2), 4,49 (d, 1 H, J = 7,0), 5,98 (širok s, 1 H), 6,83 (širok s, 1 H), 7,33 Q'asen s, 7 H), 7,70 (s, 1 H);Ή NMR 2.56 (dt, 1 H, J = 3.2,11.6), 2.67 and 3.16 (AB q, 2H, J = 16.4), 2.96 (dt, 1 H) , J = 12.0, 1.6), 3.30 (d, 1 H, J = 7.0), 3.86 (dt, 1 H, J = 3.2, 12.0), 4, 08 (ddt, 1H, J = 11.6, 3.2.1.6), 4.48 and 4.84 (AB q, 2H, J = 13.2), 4.49 (d, 1 H, J = 7.0), 5.98 (broad s, 1 H), 6.83 (wide s, 1 H), 7.33 Q'asen s, 7 H), 7.70 (s, 1 H);

IR (čist) 3445, 2838,1682,1278,1173,1132,760, 704, 682;IR (pure) 3445, 2838,1682,1278,1173,1132,760, 704, 682;

FAB-MS 463 (M+l)+.FAB-MS 463 (M + 1) + .

Analiza za C21H2QF6NO3: izrač.: C 54,54;Analysis for C 21 H 2Q F 6 NO 3 : Calc .: C 54.54;

ugot.: C 54,54;Found: C, 54.54;

H 4,36; H 4,52;H, 4.36; H, 4.52;

N 6,06; N 5,61;N, 6.06; N, 5.61;

F 24,65; F 24,45.F 24.65; F 24.45.

Podoben poizkus izvedemo na 40 mg (0,99 mmol) cis-izomera (+/-)-2-(3,5-bis(trifluorometil)-benziloksi)-3-fenil-morfolina (primer 4), pri čemer v reakciji uporabimo 0,035 ml (0,2 mmol) Ν,Ν-diizopropiletilamina in 37 mg (0,2 mmol) jodoacetamida. Obdelava in flash kromatografija da 30 mg (65 %) cis-izomera naslovne spojine kot olje:A similar experiment was performed on 40 mg (0.99 mmol) of the cis-isomer of (+/-) - 2- (3,5-bis (trifluoromethyl) -benzyloxy) -3-phenyl-morpholine (Example 4), wherein in the reaction 0.035 ml (0.2 mmol) of Ν, Ν-diisopropylethylamine and 37 mg (0.2 mmol) of iodoacetamide are used. Treatment and flash chromatography gave 30 mg (65%) of the cis-isomer of the title compound as an oil:

Ή NMR 2,54 in 3,04 (AB q, 2 H, J = 16,8), 2,63 (dt, 1 H, J = 3,6, 12,0), 3,04 (d, 1 H, J = 11,6), 3,65 (d, 1 H, J = 2,8), 3,71 (ddt, 1 H, J = 11,6, 3,2,1,2), 4,21 (dt, 1 H, J = 11,6,2,4), 4,44 in 4,89 (AB q, 2 H, J = 13,6), 4,71 (d, 1 H, J = 2,8), 5,86 (širok s, 1 H), 7,15 (širok s, 1 H), 7,27 - 7,45 (7 H), 7,73 (s, 1 H);Ή NMR 2.54 and 3.04 (AB q, 2 H, J = 16.8), 2.63 (dt, 1 H, J = 3.6, 12.0), 3.04 (d, 1 H, J = 11.6), 3.65 (d, 1 H, J = 2.8), 3.71 (ddt, 1 H, J = 11.6, 3.2,1,2), 4 , 21 (dt, 1 H, J = 11,6,2,4), 4,44 and 4,89 (AB q, 2 H, J = 13,6), 4,71 (d, 1 H, J = 2.8), 5.86 (broad s, 1 H), 7.15 (broad s, 1 H), 7.27 - 7.45 (7 H), 7.73 (s, 1 H);

FAB-MS 463(M+1)+.FAB-MS 463 (M + 1) &lt; + &gt;.

PRIMER 6 (+/-)-2-(3,5-bis (trifluorometil)benziloksi)-3-fenil-4-(metoksikarbonilmetil)morfolinEXAMPLE 6 (+/-) - 2- (3,5-bis (trifluoromethyl) benzyloxy) -3-phenyl-4- (methoxycarbonylmethyl) morpholine

Raztopino 150 mg (0,37 mmol) trans-izomera (+/-)-2-(3,5-bis(trifluorometil)benziloksi)-3-fenil morfolina (primer 4) (R1 = H) in 0,18 ml (1,00 mmol) Ν,Νdiizopropiletilamina v 2 ml acetonitrila obdelamo z 0,095 ml (1,00 mmol) metil bromoacetata in nastalo raztopino mešamo 20 h pri sobni temperaturi. Raztopino koncentriramo v vakuumu in ostanek porazdelimo med 20 ml etil acetata in 5 ml 0,5 N vodne raztopine kalijevega hidrogen sulfata. Plasti ločimo; organsko plast speremo z 10 ml nasičene vodne raztopine natrijevega klorida, posušimo preko magnezijevega sulfata in koncentriramo v vakuumu. Flash kromatografija na 10 g silikagela, pri čemer uporabimo 4 : 1 v/v heksane/eter kot eluent, da 164 mg (93 %) trans-izomera naslovne spojine kot olje:A solution of 150 mg (0.37 mmol) trans-isomer (+/-) - 2- (3,5-bis (trifluoromethyl) benzyloxy) -3-phenyl morpholine (Example 4) (R 1 = H) and 0.18 ml (1.00 mmol) of diisopropylethylamine in 2 ml of acetonitrile was treated with 0.095 ml (1.00 mmol) of methyl bromoacetate and the resulting solution was stirred for 20 h at room temperature. The solution was concentrated in vacuo and the residue partitioned between 20 ml of ethyl acetate and 5 ml of 0.5 N aqueous potassium hydrogen sulphate solution. The layers are separated; The organic layer was washed with 10 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 10 g of silica gel using 4: 1 v / v hexanes / ether as eluant to give 164 mg (93%) of the trans isomer of the title compound as an oil:

Ή NMR 2,79 (dt, 1 H, J = 3,2, 11,2), 2,93 (dt, 1 H, J = 11,2, 1,6), 3,52 (d, 1 H, J = 7,2), 3,63 (s, 3 H), 3,92 (dt, 1 H, J = 2,8,11,6), 4,04 (ddd, 1 H, J = 11,6, 3,2,1,6), 4,45 in 4,84 (AB q, 2 H, J = 13,2), 4,46 (d, 1 H, J = 7,2), 7,31 - 7,38 (m, 6 H), 7,68 (s, 1 H);Ή NMR 2.79 (dt, 1 H, J = 3.2, 11.2), 2.93 (dt, 1 H, J = 11.2, 1.6), 3.52 (d, 1 H) , J = 7.2), 3.63 (s, 3 H), 3.92 (dt, 1 H, J = 2.8, 11.6), 4.04 (ddd, 1 H, J = 11) , 6, 3,2,1,6), 4,45 and 4,84 (AB q, 2 H, J = 13,2), 4,46 (d, 1 H, J = 7,2), 7 , 31-7.38 (m, 6H), 7.68 (s, 1H);

IR (čist) 2861,1744,1455,1375,1346,1278,1170,887, 759, 704, 682;IR (pure) 2861,1744,1455,1375,1346,1278,1170,887, 759, 704, 682;

FAB-MS 478(M+1)+.FAB-MS 478 (M + 1) &lt; + &gt;.

Analiza za CLHLKNO,:Analysis for CLHLKNO,:

izrač.: C 55,35; H 4,43; N 2,93; F 23,88;Calc'd: C, 55.35; H, 4.43; N, 2.93; F, 23.88;

ugot.: C 55,74; H 4,50; N 2,79; F 24,01.found: C 55.74; H, 4.50; N, 2.79; F 24.01.

PRIMER 7EXAMPLE 7

N-metoksi-N-metil-(N-t-butoksikarbonil)-fenil-glicinamidN-methoxy-N-methyl- (N-t-butoxycarbonyl) -phenyl-glycinamide

Raztopino 20,0 g (79,7 mmol) (N-t-butoksikarbonil)fenilglicina v 150 ml etil acetata pri -10 °C obdelamo z 8,8 ml (79,7 mmol) 4-metilmorfolina. Po kapljicah dodamo izobutilkloroformat (10,3 ml, 79,7 mmol) v 10 minutah, pri čemer vzdržujemo temperaturo pri -10 °C; nastalo suspenzijo hladno mešamo 15 min. Zmes obdelamo z 11,6 ml (119,0 mmol) Ν,Ο-dimetilhidroksilamina . HC1. Dodamo drug del 4-metilmorofolino (13,0 ml, 119,0 mmol) in reakcijsko zmes mešamo 15 min. pri -10 °C in 2 h pri 25 °C. Reakcijsko zmes porazdelimo med 100 ml etil acetata in 100 ml 10 % vodne raztopine citronske kisline in plasti ločimo. Organsko plast speremo s 100 ml nasičene vodne raztopine natrijevega bikarbonata, 100 ml nasičene vodne raztopine amonijevega klorida, posušimo preko magnezijevega sulfata in koncentriramo v vakuumu. Kristalizacija iz heksanov pri -20 °C v 72 h da 8,0 g (34 %) naslovne spojine kot trdne snovi:A solution of 20.0 g (79.7 mmol) of (N-t-butoxycarbonyl) phenylglycine in 150 ml of ethyl acetate at -10 ° C was treated with 8.8 ml (79.7 mmol) of 4-methylmorpholine. Isobutyl chloroformate (10.3 mL, 79.7 mmol) was added dropwise over 10 minutes while maintaining the temperature at -10 ° C; the resulting suspension was stirred cold for 15 min. The mixture was treated with 11.6 ml (119.0 mmol) of N, N-dimethylhydroxylamine. HC1. Another portion of 4-methylmorpholino (13.0 mL, 119.0 mmol) was added and the reaction was stirred for 15 min. at -10 ° C and 2 h at 25 ° C. The reaction mixture was partitioned between 100 ml of ethyl acetate and 100 ml of 10% aqueous citric acid and the layers were separated. The organic layer was washed with 100 ml of saturated aqueous sodium bicarbonate solution, 100 ml of saturated aqueous ammonium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Crystallization from hexanes at -20 ° C for 72 h yields 8.0 g (34%) of the title compound as a solid:

Ή NMR 1,40 (s, 9 H), 3,20 (s, 3 H), 3,40 (s, 3 H), 5,80 (m, 2 H), 7,40 (m, 5 H).Ή NMR 1.40 (s, 9 H), 3.20 (s, 3 H), 3.40 (s, 3 H), 5.80 (m, 2 H), 7.40 (m, 5 H) ).

PRIMER 8EXAMPLE 8

Dietil (2-okso-3-t-butoksikarbamido-3-fenil)-propilfosfonatDiethyl (2-oxo-3-t-butoxycarbamido-3-phenyl) -propylphosphonate

Raztopino 7,45 ml (51,0 mmol) dietil metilfosfonata v tetrahidrofuranu pri -78 °C obdelamo z 31,8 ml (51,0 mmol) 1,6 M n-butillitija v heksanski raztopini in nastalo zmes hladno mešamo 30 min. Dodamo raztopino 4,0 g (14,0 mmol) N-metoksi-Nmetil-(N-t-butoksikarbonil)fenil-glicinamida (primer 7) v 20 ml tetrahidrofurana in reakcijsko zmes mešamo 15 min. pri -78 °C in 15 min. pri 25 °C. Reakcijsko zmes pogasimo s 150 ml nasičene vodne raztopine amonijevega klorida, razredčimo s 300 ml etil acetata in plasti ločimo. Organsko plast posušimo preko magnezijevega sulfata in koncentriramo v vakuumu. Flash kromatografija na silikagelu, pri čemer uporabimo 7 : 3 v/v nato 4 :1 v/v etil acetat/heksane kot eluent, da 4,8 g (92 %) naslovne spojine kot olje:A solution of 7.45 ml (51.0 mmol) of diethyl methylphosphonate in tetrahydrofuran at -78 ° C was treated with 31.8 ml (51.0 mmol) of 1.6 M n-butyllithium in hexane solution and the resulting mixture was stirred cold for 30 min. A solution of 4.0 g (14.0 mmol) of N-methoxy-Nmethyl- (N-t-butoxycarbonyl) phenyl-glycinamide (Example 7) in 20 ml of tetrahydrofuran was added and the reaction mixture was stirred for 15 min. at -78 ° C and 15 min. at 25 ° C. The reaction mixture was quenched with 150 ml of saturated aqueous ammonium chloride solution, diluted with 300 ml of ethyl acetate and the layers separated. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on silica gel using 7: 3 v / v then 4: 1 v / v ethyl acetate / hexanes as eluent to give 4.8 g (92%) of the title compound as an oil:

JH NMR 1,20 - 1,42 (15 H), 2,84 (dd, 1 H), 3,20 (dd, 1 H), 4,00 - 4,20 (m, 4 H), 5,50 (d, 1 H), 5,94 (širok s, 1 H), 7,32 (m, 5 H). 1 H NMR 1.20 - 1.42 (15 H), 2.84 (dd, 1 H), 3.20 (dd, 1 H), 4.00 - 4.20 (m, 4 H), 5 , 50 (d, 1 H), 5.94 (broad s, 1 H), 7.32 (m, 5 H).

PRIMER 9EXAMPLE 9

N-t-butoksikarbonil-l-fenil-2-okso-4-(3,5-bis(trifluorometil)fenil)-but-3-enaminN-t-Butoxycarbonyl-1-phenyl-2-oxo-4- (3,5-bis (trifluoromethyl) phenyl) -but-3-enamine

Raztopino 4,80 g (12,5 mmol) dietil (2-okso-3-t-butoksikarbamido-3-fenil)propilfosfonata (primer 8) v 20 ml THF po kapljicah dodamo k suspenziji 1,05 g (26,3 mmol, 60 %-na disperzija v mineralnem olju) natrijevega hidrida v 30 ml tetrahidrofurana pri 0 °C. Po 15 min. počasi dodamo 2,06 ml (12,5 mmol) 3,5-bis(trifluorometil)benzaldehida in nastalo zmes hladno mešamo 15 min. Reakcijsko zmes pogasimo s 50 ml nasičene vodne raztopine amonijevega klorida, razredčimo s 50 ml etil acetata in plasti ločimo. Organsko plast posušimo preko magnezijevega sulfata in koncentriramo v vakuumu. Flash kromatografija na silikagelu, pri čemer uporabimo 19 : 1 v/v, nato 9 : 1 v/v etil acetat/petrol eter kot eluent, da 3,30 g (56 %) naslovne spojine kot trdne snovi:A solution of 4.80 g (12.5 mmol) of diethyl (2-oxo-3-t-butoxycarbamido-3-phenyl) propylphosphonate (Example 8) in 20 ml of THF was added dropwise to a suspension of 1.05 g (26.3 mmol) , 60% dispersion in mineral oil) of sodium hydride in 30 ml of tetrahydrofuran at 0 ° C. After 15 min. 2.06 ml (12.5 mmol) of 3,5-bis (trifluoromethyl) benzaldehyde were slowly added and the resulting mixture was stirred cold for 15 min. The reaction mixture was quenched with 50 ml of saturated aqueous ammonium chloride solution, diluted with 50 ml of ethyl acetate and the layers separated. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on silica gel using 19: 1 v / v then 9: 1 v / v ethyl acetate / petroleum ether as eluent to give 3.30 g (56%) of the title compound as a solid:

Ή NMR 1,40 (s, 9 H), 5,38 (d, 1 H), 5,90 (d, 1 H), 6,80 (d, 1 H), 7,39 (m, 5 H), 7,70 (s, 1 H), 7,84 (s, 3 H).Ή NMR 1.40 (s, 9 H), 5.38 (d, 1 H), 5.90 (d, 1 H), 6.80 (d, 1 H), 7.39 (m, 5 H) ), 7.70 (s, 1H), 7.84 (s, 3H).

PRIMER 10 l-fenil-2-hidroksi-4-(3,5-bis(trifluorometil)fenil)-but-3-enamin. HC1EXAMPLE 10 1-Phenyl-2-hydroxy-4- (3,5-bis (trifluoromethyl) phenyl) -but-3-enamine. HC1

Raztopino 1,00 g (2,1 mmol) N-t-butoksikarbonil-l-fenil-2-okso-4-(3,5-bis(trifluorometil)fenil)-but-3-enamina (primer 8) v 30 ml metanola pri 0 °C obdelamo s 241 mg (6,3 mmol) natrijevega borohidrida. Po 30 min. reakcijsko zmes pogasimo s 50 ml vode in koncentriramo v vakuumu, da odstranimo metanol. Zmes porazdelimo med 100 ml etil acetata in 50 ml vode in plasti ločimo. Organsko plast posušimo preko magnezijevega sulfata in koncentriramo v vakuumu. Kristalizacija iz etra/heksanov da 680 mg (68 %) naslovne spojine kot 5 :1 zmesi diastereomerov (vsak zaščiten kot t-butilkarbamat):A solution of 1.00 g (2.1 mmol) of Nt-butoxycarbonyl-1-phenyl-2-oxo-4- (3,5-bis (trifluoromethyl) phenyl) -but-3-enamine (Example 8) in 30 ml of methanol at 0 ° C was treated with 241 mg (6.3 mmol) of sodium borohydride. After 30 min. The reaction mixture was quenched with 50 ml of water and concentrated in vacuo to remove methanol. The mixture was partitioned between 100 ml of ethyl acetate and 50 ml of water and the layers separated. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Crystallization from ether / hexanes gave 680 mg (68%) of the title compound as a 5: 1 mixture of diastereomers (each protected as t-butylcarbamate):

*H NMR (* označuje resonance manjšega diastereomera) 1,40 (s, 9 H), 4,60 (dd, 1 H), 4,90 (širok s, 1 H), 5,20 (širok d, 1 H), 6,30 (dd, 1 H), 6,40 (dd, 1 H*), 6,70 (dd, 1 H), 6,80 (dd, 1 H*), 7,40 (m, 5 H), 7,80 (m, 3 H).* H NMR (* indicates small diastereomer resonances) 1.40 (s, 9 H), 4.60 (dd, 1 H), 4.90 (broad s, 1 H), 5.20 (broad d, 1 H) ), 6.30 (dd, 1 H *), 6.40 (dd, 1 H *), 6.70 (dd, 1 H *), 6.80 (dd, 1 H *), 7.40 (m, 5 H), 7.80 (m, 3 H).

Raztopino BOC-zaščitene naslovne spojine v metanolu (nasičenem z HC1) pustimo stati 72 h. Raztopino koncentriramo v vakuumu. Prekristalizacija iz nastale trdne snovi iz etra/heksana da 500 mg (80 %) naslovne spojine. HC1, kot trdne snovi:A solution of the BOC-protected title compound in methanol (saturated with HCl) was allowed to stand for 72 h. The solution was concentrated in vacuo. Recrystallization from the resulting ether / hexane solid gave 500 mg (80%) of the title compound. HC1 as solids:

NMR 4,20 (širok s, 1 H), 4,40 (d, 1 H), 6,20 (dd, 1 H), 6,60 (dd, 1 H), 7,30 (m, 5 H), 7,80 (m, 3 H).NMR 4.20 (broad s, 1 H), 4.40 (d, 1 H), 6.20 (dd, 1 H), 6.60 (dd, 1 H), 7.30 (m, 5 H) ), 7.80 (m, 3H).

Naslovno spojino . HC1 raztopimo v etil acetatu in 1 N vodni raztopini natrijevega hidroksida. Plasti ločimo; organsko plast posušimo preko magnezijevega sulfata in koncentriramo v vakuumu, da dobimo naslovno spojino kot prosto bazo.The title compound. HCl was dissolved in ethyl acetate and 1 N aqueous sodium hydroxide solution. The layers are separated; the organic layer was dried over magnesium sulfate and concentrated in vacuo to give the title compound as the free base.

PRIMER 11EXAMPLE 11

2- (2-(3,5-bis(trifluorometil)fenil)etenil)-3-fenil-5-okso-morfolin2- (2- (3,5-bis (trifluoromethyl) phenyl) ethenyl) -3-phenyl-5-oxo-morpholine

Raztopino 1,95 g (5,2 mmol) l-fenil-2-hidroksi-4-(3,5-bis(trifluorometil)fenil-but-3enamina (primer 10) v 20 ml toluena dodamo k suspenziji 250 mg (6,2 mmol, 60 % disperzija v mineralnem olju) natrijevega hidrida v 30 ml toluena in nastalo zmes mešamo 15 min. pri sobni temperaturi. Počasi dodamo raztopino 0,60 ml (1,15 mol) etil kloroacetata v 5 ml toluena in nastalo zmes segrevamo 3 h pri refluksu. Reakcijsko zmes ohladimo, pogasimo s 50 ml nasičene vodne raztopine amonijevega klorida, razredčimo s 50 ml etil acetata in plasti ločimo. Organsko plast posušimo preko magnezijevega sulfata in koncentriramo v vakuumu. Flash kromatografija, pri čemer uporabimo etil acetat/heksane (4 : 1 v/v, nato 3 : 1 v/v, nato 1: 1 v/v) nato etil acetat kot eluent, da 300 mg trans-naslovne spojine in 800 mg cis-naslovne spojine (55 % celokupno), obe kot trdni snovi.A solution of 1.95 g (5.2 mmol) of 1-phenyl-2-hydroxy-4- (3,5-bis (trifluoromethyl) phenyl-but-3enamine (Example 10) in 20 ml of toluene was added to a suspension of 250 mg (6 , 2 mmol, 60% dispersion in mineral oil) of sodium hydride in 30 ml of toluene and the resulting mixture was stirred for 15 minutes at room temperature. A solution of 0.60 ml (1.15 mol) of ethyl chloroacetate in 5 ml of toluene was slowly added and the resulting mixture The reaction mixture was cooled, quenched with 50 ml of saturated aqueous ammonium chloride solution, diluted with 50 ml of ethyl acetate, and the layers were separated. hexanes (4: 1 v / v, then 3: 1 v / v, then 1: 1 v / v) then ethyl acetate as eluent to give 300 mg of trans-title compound and 800 mg of cis-title compound (55% overall) , both as solids.

Za cis-izomer: Ή NMR 1,20 - 1,40 (m, 1 H), 1,50 - 1,62 (m, 1 H), 2,60 - 2,98 (m, 2 H), 3,86 (dt, 1 H), 4,24 (d, 1 H), 4,34 (dd, 1 H), 4,45 (d, 1 H), 6,40 (širok s, 1 H), 7,24 (m, 2 H), 7,40 (m, 3 H), 7,50 (s, 2 H), 7,70 (s, 1 H).For the cis isomer: Ή NMR 1.20 - 1.40 (m, 1 H), 1.50 - 1.62 (m, 1 H), 2.60 - 2.98 (m, 2 H), 3 , 86 (dt, 1H), 4.24 (d, 1H), 4.34 (dd, 1H), 4.45 (d, 1H), 6.40 (broad s, 1H), 7.24 (m, 2 H), 7.40 (m, 3 H), 7.50 (s, 2 H), 7.70 (s, 1 H).

PRIMER 12EXAMPLE 12

3- fenil-2-(2-(3,5-bis(trifluorometil)fenil)etil)-morfolin3-phenyl-2- (2- (3,5-bis (trifluoromethyl) phenyl) ethyl) -morpholine

Raztopino 95 mg (0,23 mmol) 2-(2-(3,5-bis(trifluorometil)fenil)etenil)-3-fenil-5okso-morfolina (primer 11) v 10 ml 1 : 1 v/v etanol/etil acetata obdelamo z 10 mg paladijevega hidroksida in nastalo zmes mešamo 2 h pod atmosfero vodika. Katalizator filtriramo in filtrat koncentriramo v vakuumu. Surovi produkt uporabimo neposredno brez nadaljnjega čiščenja.95 mg (0.23 mmol) solution of 2- (2- (3,5-bis (trifluoromethyl) phenyl) ethenyl) -3-phenyl-5-oxo-morpholine (Example 11) in 10 ml of 1: 1 v / v ethanol / ethyl acetate was treated with 10 mg of palladium hydroxide and the resulting mixture was stirred for 2 h under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated in vacuo. The crude product is used directly without further purification.

Raztopino 65 mg surovega morfolina raztopimo v 10 ml tetrahidrofurana, obdelamo z 0,84 ml 1 M raztopine boran.tetrahidrofuranskega kompleksa v tetrahidrofuranu in nastalo raztopino segrevamo 16 h pri refluksu. Reakcijsko zmes pogasimo z dodajanjem 10 ml metanola in 70 mg kalijevega karbonata in segrevanjem nastale zmesi 3 h pri refluksu. Vse hlapne snovi odstranimo v vakuumu in ostanek porazdelimo med 20 ml etil acetata in 10 ml nasičene raztopine amonijevega klorida. Organsko plast ločimo, posušimo preko natrijevega karbonata in koncentriramo v vakuumu. Ostanek raztopimo v nasičeni HCl v metanolu in koncentriramo v vakuumu. Ostanek trituriramo z etrom; nastalo trdno snov filtriramo in posušimo, da dobimo 32 mg (46 %) naslovne spojine . HCl, tal. 114 do 116 °C:A solution of 65 mg of crude morpholine was dissolved in 10 ml of tetrahydrofuran, treated with 0.84 ml of a 1 M solution of borane tetrahydrofuran complex in tetrahydrofuran, and the resulting solution heated at reflux for 16 h. The reaction mixture was quenched by adding 10 ml of methanol and 70 mg of potassium carbonate and heating the resulting mixture for 3 h at reflux. All volatiles were removed in vacuo and the residue was partitioned between 20 ml of ethyl acetate and 10 ml of saturated ammonium chloride solution. The organic layer was separated, dried over sodium carbonate and concentrated in vacuo. The residue was dissolved in saturated HCl in methanol and concentrated in vacuo. The residue was triturated with ether; the resulting solid was filtered and dried to give 32 mg (46%) of the title compound. HCl, m.p. 114 to 116 ° C:

Ή NMR 1,42 (m, 1 H), 1,66 -1,84 (m, 1 H), 2,70 - 2,94 (m, 2 H), 3,00 (m, 1 H), 3,30 3,46 (m, 1 H), 3,80 - 3,94 (m, 2 H), 4,10 (m, 1 H), 4,20 (d, 1 H), 7,40 (m, 3 H), 7,64 (m, 5 H);Ή NMR 1.42 (m, 1 H), 1.66 -1.84 (m, 1 H), 2.70 - 2.94 (m, 2 H), 3.00 (m, 1 H), 3.30 3.46 (m, 1 H), 3.80 - 3.94 (m, 2 H), 4.10 (m, 1 H), 4.20 (d, 1 H), 7.40 (m, 3 H), 7.64 (m, 5 H);

CI-MS 402(M+l)+.CI-MS 402 (M + 1) &lt; + &gt;.

PRIMER 13EXAMPLE 13

N-benzil-(S)-fenilglicinN-benzyl- (S) -phenylglycine

Raztopino 1,51 g (10,0 mmol) (S)-fenilglicina v 5 ml 2 N vodne raztopine natrijevega hidroksida obdelamo z 1,0 ml (10,0 mmol) benzaldehida in mešamo 20 minut pri sobni temperaturi. Raztopino razredčimo s 5 ml metanola, ohladimo na 0 °C in previdno obdelamo z 200 mg (5,3 mmol) natrijevega borohidrida. Hladilno kopel odstranimo in reakcijsko zmes mešamo 1,5 ure pri sobni temperaturi. Reakcijsko zmes razredčimo z 20 ml vode in ekstrahiramo z 2 x 25 ml metilenklorida. Vodno plast nakisamo s koncentrirano klorovodikovo kislino do pH 6 in trdno snov, ki se obori, filtriramo, speremo s 50 ml vode, 50 ml 1:1 v/v metanola/etil etra in 50 ml etra in posušimo, da dobimo 1,83 g (76 %) produkta, tal. 230 do 232 °C.A solution of 1.51 g (10.0 mmol) of (S) -phenylglycine in 5 ml of 2 N aqueous sodium hydroxide solution was treated with 1.0 ml (10.0 mmol) of benzaldehyde and stirred for 20 minutes at room temperature. The solution was diluted with 5 ml of methanol, cooled to 0 ° C and carefully treated with 200 mg (5.3 mmol) of sodium borohydride. The cooling bath was removed and the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with 20 ml of water and extracted with 2 x 25 ml of methylene chloride. The aqueous layer was acidified with concentrated hydrochloric acid to pH 6 and the precipitated solid was filtered, washed with 50 ml of water, 50 ml of 1: 1 v / v methanol / ethyl ether and 50 ml of ether and dried to give 1.83 g (76%) of the product, m.p. 230 to 232 ° C.

Analiza za C15H15NO2: izrač. C 74,66 ugot. C 74,17Analysis for C 15 H 15 NO 2 : calc. C 74.66 found C, 74.17

N 5,81 N 5,86N, 5.81; N, 5.86

H 6,27 H 6,19H 6.27 H 6.19

PRIMER 14EXAMPLE 14

3-(S)-fenil-4-benzil-2-morfolinon3- (S) -phenyl-4-benzyl-2-morpholinone

Zmes 4,00 g (16,6 mmol) N-benzil-(S)-fenilglicina (iz primera 13), 5,00 g (36,0 mmol) kalijevega karbonata, 10,0 ml 1,2-dibromoetana in 25 ml N,Ndimetilformamida mešamo 20 h pri 100 °C. Zmes ohladimo in porazdelimo med 200 ml etil etra in 100 ml vode. Plasti ločimo in organsko plast speremo s 3 x 50 ml vode, posušimo preko magnezijevega sulfata in koncentriramo v vakuumu. Ostanek prečistimo s flash kromatografijo na 125 g silikagela, pri čemer eluiramo z 9 : 1 v/v, nato 4 : 1 v/v heksani/etil etrom, da dobimo 2,41 g (54 %) produkta kot trdno snov, tal. 98 do 100 °C.Mixture of 4.00 g (16.6 mmol) of N-benzyl- (S) -phenylglycine (from Example 13), 5.00 g (36.0 mmol) of potassium carbonate, 10.0 ml of 1,2-dibromoethane and 25 ml of N, N-dimethylformamide was stirred for 20 h at 100 ° C. The mixture was cooled and partitioned between 200 ml of ethyl ether and 100 ml of water. The layers were separated and the organic layer was washed with 3 x 50 ml of water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on 125 g of silica gel eluting with 9: 1 v / v then 4: 1 v / in hexanes / ethyl ether to give 2.41 g (54%) of the product as a solid, m.p. 98 to 100 ° C.

Masni spekter (FAB): m/z 268 (M+H, 100 %).Mass spectrum (FAB): m / z 268 (M + H, 100%).

*H NMR (CDC13, 200 MHz, ppm): d 2,54 - 2,68 (m, 1 H), 2,96 (dt, J = 12,8, 2,8,1 H), 3,14 (d, J = 13,3,1 H), 3,75 (d, J = 13,3,1 H), 4,23 (s, 1 H), 4,29 - 4,37 (m, 1 H), 4,53 (dt, J = 3,2,11,0), 7,20 - 7,56 (m, 10 H).1 H NMR (CDCl 3 , 200 MHz, ppm): d 2.54 - 2.68 (m, 1 H), 2.96 (dt, J = 12.8, 2.8.1 H), 3. 14 (d, J = 13.3.1 H), 3.75 (d, J = 13.3.1 H), 4.23 (s, 1 H), 4.29 - 4.37 (m, 1 H), 4.53 (dt, J = 3.2, 11.0), 7.20 - 7.56 (m, 10 H).

Analiza za C17H1?NO2:Analysis for C 17 H 1? NO 2 :

izrač. C 76,38 H 6,41 N 5,24 ugot. C 76,06 H 6,40 N 5,78calcd. C 76.38 H 6.41 N 5.24 found. C 76.06 H 6.40 N 5.78

PRIMER 15EXAMPLE 15

2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenilmorfolin2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenylmorpholine

Korak A 3,5-bis(trifluorometil)benzil alkohol, trifluorometansulfonatni esterStep A 3,5-bis (trifluoromethyl) benzyl alcohol, trifluoromethanesulfonate ester

Raztopino 1,00 g (4,1 mmol) 3,5-bis(trifluorometil)benzil alkohola in 1,05 g (5,12 mmol) 2,6-di-t-butil-4-metilpiridina v 45 ml suhega ogljikovega tetraklorida pod atmosfero dušika obdelamo z 0,74 ml (4,38 mmol) trifluorometansulfonskega anhidrida pri sobni temperaturi. Kmalu po dodatku anhidrida se tvori bela oborina. Po 90 min. suspenzijo filtriramo pod dušikom s Schlenk-ovim filtrom in filtrat koncentriramo v vakuumu. Ostanek, kije dvo-fazno olje, raztopimo pod dušikom v 10 ml suhega toluena. Nastalo bistro raztopino uporabimo neposredno v koraku B spodaj.A solution of 1.00 g (4.1 mmol) of 3,5-bis (trifluoromethyl) benzyl alcohol and 1.05 g (5.12 mmol) of 2,6-di-t-butyl-4-methylpyridine in 45 ml of dry carbon of the tetrachloride under a nitrogen atmosphere was treated with 0.74 ml (4.38 mmol) of trifluoromethanesulfonic anhydride at room temperature. A white precipitate forms soon after the anhydride is added. After 90 min. the suspension was filtered under nitrogen with a Schlenk filter and the filtrate was concentrated in vacuo. The residue, which is a two-phase oil, is dissolved under nitrogen in 10 ml of dry toluene. The resulting clear solution is used directly in step B below.

Korak B 4-benzil-2-(S)-(3,5-bis(trifIuorometil)benziloksi)-3-(S)-fenilmorfolinStep B 4-Benzyl-2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenylmorpholine

Raztopino 0,500 g (1,87 mmol) N-benzil-3-(S)-fenilmorfolin-2-ona (iz primera 14) v 10 ml suhega THF ohladimo do -75 °C pod dušikom in po kapljicah obdelamo z 2,06 ml (2,06 mmola) IM raztopine litijevega tri(sek.-butil)-borohidrida (L-Selectride®) v THF. Po mešanju raztopine 30 min. pri -75 °C, dodamo po cevki raztopino 3,5bis(trifluorometil)benzil alkohola, trifluorometansulfonatnega estera v toluenu tako da notranjo temperaturo vzdržujemo pod -60 °C. Nastalo raztopino mešamo 1 h pri -75 °C in nato 2 h med -38 °C in -50 °C. Raztopino nato zlijemo v zmes 25 ml etil acetata in 20 ml nasičenega vodnega natrijevega bikarbonata, in plasti ločimo. Vodno fazo ekstrahiramo z 2 x 30 ml etil acetata, združene organske plasti posušimo preko natrijevega sulfata, zmes filtriramo in filtrat koncentriramo v vakuumu. Ostanek prečistimo s flash kromatografijo na 130 g kremenice, pri čemer eluiramo z 21100.5 heksani.etil acetat, da dobimo 0,68 g (73 %) olja, kije z Ή NMR 20 :1 zmes cis:trans morfolinov.A solution of 0.500 g (1.87 mmol) of N-benzyl-3- (S) -phenylmorpholin-2-one (Example 14) in 10 ml of dry THF was cooled to -75 ° C under nitrogen and treated with 2.06 drops ml (2.06 mmol) of IM solution of lithium tri (sec-butyl) -borohydride (L-Selectride®) in THF. After stirring the solution for 30 min. at -75 ° C, a solution of 3.5bis (trifluoromethyl) benzyl alcohol, trifluoromethanesulfonate ester in toluene is added over the tube so that the internal temperature is maintained below -60 ° C. The resulting solution was stirred for 1 h at -75 ° C and then between -38 ° C and -50 ° C for 2 h. The solution was then poured into a mixture of 25 ml of ethyl acetate and 20 ml of saturated aqueous sodium bicarbonate, and the layers were separated. The aqueous phase is extracted with 2 x 30 ml ethyl acetate, the combined organic layers are dried over sodium sulfate, the mixture is filtered and the filtrate is concentrated in vacuo. The residue was purified by flash chromatography on 130 g of silica eluting with 21100.5 hexanes.ethyl acetate to give 0.68 g (73%) of the oil, which was treated with Ή NMR 20: 1 mixture of cis: trans morpholines.

1H NMR (CDC13, 400 MHz, ppm): δ večina (cis) izomer:2,37 (td, J = 12, 3,6, 1 H), 2,86 (jasen t, J = 13, 2 H), 3,57 (d, J = 2,6,1 H), 3,63 (dq, J = 11,3,1,6,1 H), 3,89 (d, J = 13,3,1 H), 4,12 (td, J = 11,6, 2,4,1 H), 4,40 (d, J = 13,6,1 H), 4,69 (d, J = 2,9, 1 H), 4,77 (d, J = 13,6), 7,2 - 7,4 (m, 8 H), 7,43 (s, 2 H), 7,55 (širok d, 2 H), 7,69 (s, 1 H)· 1 H NMR (CDCl 3 , 400 MHz, ppm): δ majority (cis) isomer: 2.37 (td, J = 12, 3.6, 1 H), 2.86 (clear t, J = 13, 2 H), 3.57 (d, J = 2.6.1 H), 3.63 (dq, J = 11.3.1.6.1 H), 3.89 (d, J = 13.3) , 1 H), 4.12 (td, J = 11.6, 2.4.1 H), 4.40 (d, J = 13.6.1 H), 4.69 (d, J = 2 , 9, 1 H), 4.77 (d, J = 13.6), 7.2 - 7.4 (m, 8 H), 7.43 (s, 2 H), 7.55 (broad d , 2 H), 7.69 (s, 1 H) ·

Korak C 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenilmorfolinStep C 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenylmorpholine

Zmes 0,68 g (1,37 mmol) 4-benzil-2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil morfolina in 280 mg 10 % Pd/C v 36 ml 97 : 3 etanola:vode mešamo 15 h pod atmosfero vodika. Zmes filtriramo preko Celite-a, filtrsko pogačo speremo obilno z etanolom in filtrat koncentriramo v vakuumu. Ostanek prečistimo s flash kromatografijo na 68 g kremenice, pri čemer eluiramo z 1133 : 67 heksanhdietil etru, nato 1 1 25 : 75 heksanhdietil etru, da dobimo 0,443 g (80 %) olja, ki je po XH NMR čisti cis morfolin.A mixture of 0.68 g (1.37 mmol) of 4-benzyl-2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl morpholine and 280 mg of 10% Pd / C in 36 ml 97: 3 ethanol: the water was stirred for 15 h under a hydrogen atmosphere. The mixture was filtered through Celite, the filter cake was washed copiously with ethanol, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on 68 g of quartz, eluting with 1133: 67 hexanhyddiethyl ether followed by 1 1 25: 75 hexane didiethyl ether to give 0.443 g (80%) of oil, which was pure cis morpholine after X H NMR.

JH NMR (CDC13, 400 MHz, ppm): δ 1,8 (širok s, 1 H), 3,10 (dd, J = 12,5, 2,9, 1 H), 3,24 (td, J = 12,2, 3,6, 1 H), 3,62 (dd, J = 11,3, 2,5, 1 H), 4,04 (td, J = 11,7, 3, 1 H), 4,11 (d, J = 2,4, 1 H), 4,49 (d, J = 13,5,1 H), 4,74 (d, J = 2,5,1 H), 4,80 (d, J = 13,3, 1 H), 7,25 - 7,40 (m, 5 H), 7,40 (s, 2 H), 7,68 (s, 1 H). 1 H NMR (CDCl 3 , 400 MHz, ppm): δ 1.8 (broad s, 1 H), 3.10 (dd, J = 12.5, 2.9, 1 H), 3.24 (td , J = 12.2, 3.6, 1 H), 3.62 (dd, J = 11.3, 2.5, 1 H), 4.04 (td, J = 11.7, 3, 1 H), 4.11 (d, J = 2.4, 1 H), 4.49 (d, J = 13.5.1 H), 4.74 (d, J = 2.5.1 H). , 4.80 (d, J = 13.3, 1 H), 7.25 - 7.40 (m, 5 H), 7.40 (s, 2 H), 7.68 (s, 1 H) .

Analiza za C19H17F6NO2: izrač. C 56,30 H 4,23 ugot. C 56,20 H 4,29Analysis for C 19 H 17 F 6 NO 2 : calc. C 56.30 H 4.23 found C 56.20 H 4.29

N 3,46 F 28,12N, 3.46; F, 28.12

N 3,34 F 27,94N, 3.34 F, 27.94

PRIMER 16EXAMPLE 16

2(R)-(3,5-bis(trifluorometil)benziloksi)-3(Rl-fenilmorfolin2 (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3 (R1-phenylmorpholine)

Naslovno spojino pripravimo iz (R)-fenilglicina z uporabo postopkov iz primerov 13, 14 in 15.The title compound was prepared from (R) -phenylglycine using the procedures of Examples 13, 14 and 15.

PRIMER 17EXAMPLE 17

4-(3-(1,2,4-triazoIo)metil)-2-(Sl-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenilmorfolin4- (3- (1,2,4-triazolo) methyl) -2- (Sl- (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenylmorpholine

Korak A N-formil-2-kloroacetamidrazonStep A N-formyl-2-chloroacetamidrazone

Raztopino 5 g (66,2 mmol) kloroacetonitrila v 30 ml suhega metanola ohladimo do dušika na 0 °C in obdelamo z 0,1 g (1,8 mmol) natrijevega metoksida. Zmes pustimo, da se segreje do sobne temperature in jo mešamo 30 min. in dodamo 0,106 ml (1,8 mmol) ocetne kisline. K nastali zmesi nato dodamo 3,9 g (64,9 mmol) mravljinčnega hidrazida, in material mešamo 30 min. Reakcijsko zmes koncentriramo v vakuumu do trdne snovi, in jo uporabimo kot tako v koraku B spodaj.A solution of 5 g (66.2 mmol) of chloroacetonitrile in 30 ml of dry methanol was cooled to nitrogen at 0 ° C and treated with 0.1 g (1.8 mmol) of sodium methoxide. The mixture was allowed to warm to room temperature and stirred for 30 min. and 0.106 ml (1.8 mmol) of acetic acid were added. 3.9 g (64.9 mmol) of formic hydrazide were then added to the resulting mixture, and the material was stirred for 30 min. The reaction mixture was concentrated in vacuo to a solid, and used as such in step B below.

Korak B 4-(3-(1,2,4-triazolo)metil)-2-(S)-(3,5-bis-(trifluorometil)benziloksi)3-(S)-fenilmorfolinStep B 4- (3- (1,2,4-triazolo) methyl) -2- (S) - (3,5-bis- (trifluoromethyl) benzyloxy) 3- (S) -phenylmorpholine

Raztopino 0,295 g (0,73 mmol) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil morfolina (iz primera 15) v 10 ml suhega DMF obdelamo z 0,302 g (2,18 mmol) brezvodnega kalijevega karbonata in nato z 0,168 g (1,24 mmol) N-formil-2kloroacetamidrazona (iz primera 17, korak A) in suspenzijo mešamo 4 h pri 60 °C. Zmes nato segrevamo 4,5 h na 120 °C. Po ohlajanju, reakcijsko zmes razredčimo z 80 ml etil acetata in organsko plast speremo s 3 x 20 ml vode. Organsko plast posušimo preko magnezijevega sulfata, filtriramo in koncentriramo v vakuumu. Ostanek prečistimo s flash kromatografijo na 67 g kremenice, pri čemer eluiramo s 1,5 1100:2 metilen klorid:metanolu, da dobimo 0,22 g rumene trdne snovi, ki jo prekristaliziramo iz heksanov/metilen klorida, da dobimo 0,213 g (60 %) bele kristalinične trdne snovi, tal. 134 do 135 °C.A solution of 0.295 g (0.73 mmol) of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl morpholine (Example 15) in 10 ml of dry DMF was treated with 0.302 g ( 2.18 mmol) of anhydrous potassium carbonate and then 0.168 g (1.24 mmol) of N-formyl-2chloroacetamidrazone (from Example 17, step A) and the suspension was stirred for 4 h at 60 ° C. The mixture was then heated to 120 ° C for 4.5 h. After cooling, the reaction mixture was diluted with 80 ml of ethyl acetate and the organic layer was washed with 3 x 20 ml of water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on 67 g of silica eluting with 1.5 1100: 2 methylene chloride: methanol to give 0.22 g of a yellow solid recrystallized from hexanes / methylene chloride to give 0.213 g (60 % white crystalline solids, m.p. 134 to 135 ° C.

Masni spekter (GFAB): m/z 487 (M+H, 100 %), 259 (35 %), 243 (65 %),Mass spectrum (GFAB): m / z 487 (M + H, 100%), 259 (35%), 243 (65%),

227 (40 %), 174 (25 %).227 (40%), 174 (25%).

Ή NMR (CDC13, 400 MHz, ppm): δ 2,67 (td, J = 11,9, 3,4, 1 H), 2,90 (širok d, J = 11,7,1 H), 3,43 (d, J = 15,2,1 H), 3,66 (jasen dd, J = 13,1,9, 2 H), 3,88 (d, J = 15,11 H), 4,17 (td, J = 11,7, 2,3,1 H), 4,42 (d, J = 13,5,1 H), 4,69 (d, J = 2,6,1 H), 4,77 (d, J = 13,5,1 H), 7,30 - 7,50 (m, 7 H), 7,70 (s, 1 H), 7,94 (s, 1 H).Ή NMR (CDCl 3 , 400 MHz, ppm): δ 2.67 (td, J = 11.9, 3.4, 1 H), 2.90 (broad d, J = 11.7.1 H), 3.43 (d, J = 15.2.1 H), 3.66 (clear dd, J = 13.1.9, 2 H), 3.88 (d, J = 15.11 H), 4 , 17 (td, J = 11.7, 2.3.1 H), 4.42 (d, J = 13.5.1 H), 4.69 (d, J = 2.6.1 H) , 4.77 (d, J = 13.5.1 H), 7.30 - 7.50 (m, 7 H), 7.70 (s, 1 H), 7.94 (s, 1 H) .

PRIMER 18EXAMPLE 18

4-(3-(5-okso-lH,4H-L2,4-triazolo)metil)-2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenilmorfolin4- (3- (5-oxo-1H, 4H-L2,4-triazolo) methyl) -2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenylmorpholine

Korak A N-metilkarboksi-2-kloroacetamidrazonStep A N-methylcarboxy-2-chloroacetamidrazone

Raztopino 5,0 g (66,2 mmol) kloroacetonitrila v 35 ml suhega metanola ohladimo do 0 °C in obdelamo z 0,105 g (1,9 mmol) natrijevega metoksida. Ledeno kopel odstranimo in zmes pustimo mešati pri sobni temperaturi 30 minut. K reakcijski zmesi nato dodamo 0,110 ml (1,9 mmol) ocetne kisline in nato 5,8 g (64,9 mmol) metil hidrazinkarboksilata. Po mešanju 30 minut na sobni temperaturi, suspenzijo koncentriramo v vakuumu in namestimo na visoko vakuumsko linijo preko noči, da dobimo 10,5 g (98 %) rumenega prahu, ki ga uporabimo v koraku C spodaj.A solution of 5.0 g (66.2 mmol) of chloroacetonitrile in 35 ml of dry methanol was cooled to 0 ° C and treated with 0.105 g (1.9 mmol) of sodium methoxide. The ice bath was removed and the mixture was allowed to stir at room temperature for 30 minutes. 0.110 ml (1.9 mmol) of acetic acid and then 5.8 g (64.9 mmol) of methyl hydrazincarboxylate are then added to the reaction mixture. After stirring for 30 minutes at room temperature, the suspension was concentrated in vacuo and placed on a high vacuum line overnight to give 10.5 g (98%) of the yellow powder used in step C below.

XH NMR (CD3OD, 400 MHz, ppm): δ 3,71 (s, 3 H), 4,06 (s, 2 H). X H NMR (CD 3 OD, 400 MHz, ppm): δ 3.71 (s, 3 H), 4.06 (s, 2 H).

Korak B 4-(2-(N-metilkarboksi-acetamidrazono)-2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenilmorfolinStep B 4- (2- (N-methylcarboxy-acetamidrazono) -2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenylmorpholine

Raztopino 2,30 g (5,7 mmol) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)fenilmorfolina (izh primera 15), 1,13 g (6,8 mmol) N-metilkarboksi-2kloroacetamidrazona (iz koraka A) in 1,50 ml (8,6 mmol) Ν,Ν-diizopropiletilamina v 25 ml acetonitrila mešamo 20 ur pri sobni temperaturi. Produkt, ki se obori, filtriramo, speremo s 5 ml ledeno hladnega acetonitrila in posušimo, da dobimo 1,83 g bele trdne snovi. Filtrat koncentriramo v vakuumu in ostanek porazdelimo med 50 ml metilen klorida in 20 ml vode. Plasti ločimo in organsko plast posušimo preko magnezijevega sulfata. Vodno plast ekstrahiramo s 50 ml metilen klorida; ekstrakt posušimo, združimo s prvotno organsko plastjo in združene organske plasti koncentriramo v vakuumu. Ostanek prečistimo s flash kromatografijo na 30 g silikagela, pri čemer eluiramo s 50 : 1 : 0,1 v/v/v metilen klorida/metanola/amonijevega hidroksida, da dobimo dodaten 1,09 g produkta (96 % celokupno).A solution of 2.30 g (5.7 mmol) of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) phenylmorpholine (ex. Example 15), 1.13 g (6.8 mmol) ) Of N-methylcarboxy-2chloroacetamidrazone (from step A) and 1.50 ml (8.6 mmol) of Ν, di-diisopropylethylamine in 25 ml of acetonitrile were stirred for 20 hours at room temperature. The precipitated product was filtered off, washed with 5 ml of ice-cold acetonitrile and dried to give 1.83 g of a white solid. The filtrate was concentrated in vacuo and the residue partitioned between 50 ml of methylene chloride and 20 ml of water. The layers were separated and the organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 50 ml of methylene chloride; the extract was dried, combined with the original organic layer, and the combined organic layers concentrated in vacuo. The residue was purified by flash chromatography on 30 g of silica gel eluting with 50: 1: 0.1 v / v methylene chloride / methanol / ammonium hydroxide to give an additional 1.09 g of product (96% total).

Masni spekter (FAB): m/Z 535 (M+H, 100 %), 462 (16 %), 291 (30 %), 226 (35 %), 173 (25 %).Mass spectrum (FAB): m / Z 535 (M + H, 100%), 462 (16%), 291 (30%), 226 (35%), 173 (25%).

Ή NMR (CDC13, 400 MHz, ppm): δ 2,53 (dt, J = 3,5,12,2,1 H), 2,59 (d, J = 14,6,1 H), 2,94 (d, J = 11,8, 1 H), 3,37 (d, J = 14,6, 1 H), 3,58 (d, J = 2,8, 1 H), 3,62 - 3,72 (m, 1 H), 3,75 (s, 3 H), 4,16 (dt, J = 2,2,11,8,1 H), 4,44 (d, J = 13,2,1 H), 4,70 (d, J = 2,8,1 H), 4,79 (d, J = 13,2), 5,55 (širok s, 2 H), 7,30 - 7,46 (m, 7 H), 7,72 (s, 1 H).Ή NMR (CDCl 3 , 400 MHz, ppm): δ 2.53 (dt, J = 3.5.12.2.1 H), 2.59 (d, J = 14.6.1 H), 2 , 94 (d, J = 11.8, 1 H), 3.37 (d, J = 14.6, 1 H), 3.58 (d, J = 2.8, 1 H), 3.62 - 3.72 (m, 1 H), 3.75 (s, 3 H), 4.16 (dt, J = 2.2.11.8.1 H), 4.44 (d, J = 13) , 2.1 H), 4.70 (d, J = 2.8.1 H), 4.79 (d, J = 13.2), 5.55 (broad s, 2 H), 7.30 - 7.46 (m, 7H), 7.72 (s, 1H).

Korak C 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-(3-(5-okso-lH,4H-l,2,4triazolo)metil)-3-(S)-fenilmorfolinStep C 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (3- (5-oxo-1H, 4H-1,2,4triazolo) methyl) -3- (S) -phenylmorpholine

Raztopino 2,89 g (5,4 mmol) 4-(2-(N-metilkarboksi-acetamidrazono)-2-(S)-(3,5bis(trifluorometil)-benziloksi)-3-(S)-fenilmorfolina (iz koraka B) v 36 ml ksilenov segrevamo 1,5 ure pri refluksu. Raztopino ohladimo in koncentriramo v vakuumu. Ostanek prevzamemo v 50 ml 3 : 1 v/v heksane/etil acetat, ki povzroči kristalizacijo produkta. Produkt filtriramo in posušimo, da dobimo 1,85 g trdne snovi. Prekristalizacija trdne snovi iz 30 ml 4 :1 v/v heksanov/etil acetat da 1,19 g čistega produkta kot belo trdno snov, tal. = 156 do 157 °C. Vse kristalizacijske tekočine združimo in koncentriramo v vakuumu. Ostanek prečistimo s flash kromatografijo na 30 g silikagela, pri čemer eluiramo s 50 : 1 : 0,1 v/v/v metilen klorid/metanol/amonijev hidroksid, da dobimo dodatnega 0,69 g trdne snovi. Tri prekristalizacije iz 20 ml 4 :1 v/v heksani/etil acetat dajo dodatno 0,39 g čistega produkta kot bele trdne snovi (58 % celokupno).A solution of 2.89 g (5.4 mmol) of 4- (2- (N-methylcarboxy-acetamidrazono) -2- (S) - (3,5bis (trifluoromethyl) -benzyloxy) -3- (S) -phenylmorpholine (from of step B) was refluxed for 36 hours in 36 ml of xylene. The solution was cooled and concentrated in vacuo. The residue was taken up in 50 ml of 3: 1 v / v hexanes / ethyl acetate, which led to the crystallization of the product. 1.85 g of solids Recrystallization of solids from 30 ml of 4: 1 in / in hexanes / ethyl acetate gives 1.19 g of pure product as a white solid, mp = 156 to 157 ° C. All crystallization liquids are combined and concentrated The residue was purified by flash chromatography on 30 g of silica gel, eluting with 50: 1: 0.1 v / v / v methylene chloride / methanol / ammonium hydroxide to give an additional 0.69 g of solid. 20 ml of 4: 1 v / in hexanes / ethyl acetate give an additional 0.39 g of pure product as a white solid (58% overall).

Masni spekter (FAB): m/Z 503 (M+H), 259 (55 %), 226 (40 %), 160 (30 %).Mass spectrum (FAB): m / Z 503 (M + H), 259 (55%), 226 (40%), 160 (30%).

*H NMR (CDC13, 400 MHz, ppm): δ 2,57 (jasen t, J = 9,6,1 H), 2,87 - 2,97 (m, 2 H), 3,58 - 3,71 (m, 3 H), 4,18 (jasen t, J = 10,4,1 H), 4,46 (d, J = 13,6), 4,68 (d, J = 2,8,1 H), 4,85 (d, J = 13,6, 1 H), 7,30 - 7,45 (m, 7 H), 7,64 (s, 1 H), 10,40 (širok s, 1 H), 10,73 (širok s, 1 H).1 H NMR (CDCl 3 , 400 MHz, ppm): δ 2.57 (clear t, J = 9.6.1 H), 2.87 - 2.97 (m, 2 H), 3.58 - 3 , 71 (m, 3 H), 4.18 (clear t, J = 10.4.1 H), 4.46 (d, J = 13.6), 4.68 (d, J = 2.8) , 1 H), 4.85 (d, J = 13.6, 1 H), 7.30 - 7.45 (m, 7 H), 7.64 (s, 1 H), 10.40 (broad s, 1H), 10.73 (broad s, 1H).

PRIMER 19EXAMPLE 19

N-(2-(R)-hidroksipropil)-fenilglicinal, 3,5-bis(trifluorometil)benzil acetalN- (2- (R) -hydroxypropyl) -phenylglycine, 3,5-bis (trifluoromethyl) benzyl acetal

Zmes 1,00 g (1,5 mmol) (+/-)-a-bromo-fenilacetaldehida, 3,5-bis(trifluorometil)benzil acetala (iz primera 12), 1,25 ml (R)-l-amino-2-propanola, 225 mg (1,5 mmol) natrijevega jodida in 3,75 ml izopropanola segrevamo pri refluksu 20 h. Raztopino ohladimo in koncentriramo na —25 % prvotnega volumna v vakuumu. Koncentrirano raztopino porazdelimo med 50 ml etra in 20 ml 2 N vodne raztopine natrijevega hidroksida in plasti ločimo. Organsko plast speremo z 20 ml nasičene vodne raztopine natrijevega klorida, posušimo preko magnezijevega sulfata in koncentriramo v vakuumu. Flash kromatografija na 50 g silikagela, pri čemer uporabimo 65 : 35 v/v eter/heksan kot eluent, da 948 mg (95 %) produkta kot 1 : 1 zmes neločljivih diastereomerov.A mixture of 1.00 g (1.5 mmol) (+/-) -? -Bromo-phenylacetaldehyde, 3,5-bis (trifluoromethyl) benzyl acetal (from Example 12), 1.25 ml (R) -1-amino -2-propanol, 225 mg (1.5 mmol) of sodium iodide and 3.75 ml of isopropanol were refluxed for 20 h. The solution was cooled and concentrated to -25% of the original volume in vacuo. The concentrated solution was partitioned between 50 ml of ether and 20 ml of 2 N aqueous sodium hydroxide solution and the layers separated. The organic layer was washed with 20 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 50 g of silica gel using 65: 35 v / v ether / hexane as eluant to afford 948 mg (95%) of the product as a 1: 1 mixture of inseparable diastereomers.

Masni spekter (FAB): m/Z 664 (M+H, 25 %), 420 (20 %), 226 (100 %).Mass spectrum (FAB): m / Z 664 (M + H, 25%), 420 (20%), 226 (100%).

PRIMER 20EXAMPLE 20

N-(2-(S)-hidroksipropil)-fenilglicinal, 3,5-bis(trifluorometil)benzil acetalN- (2- (S) -hydroxypropyl) -phenylglycine, 3,5-bis (trifluoromethyl) benzyl acetal

S substitucijo (R)-l-amino-2-propanola s (S)-l-amino-2-propanolom v poizkusu enakem predhodnemu primeru, dobimo 940 mg (95 %) produkta kot 1:1 zmes diastereomerov.Substitution of (R) -1-amino-2-propanol with (S) -1-amino-2-propanol in the same manner as in the preceding example gave 940 mg (95%) of the product as a 1: 1 mixture of diastereomers.

PRIMER 21EXAMPLE 21

N-(2-(R)-hidroksipropil)-N-(prop-2-enil)-(R)-fenilglicinal, 3,5bis(trifluorometil)benzil acetal in N-(2-(R)-hidroksipropil)-N-(prop-2-enil)-(S)fenilglicinal, 3,5-bis(trifluorometil)benzil acetalN- (2- (R) -hydroxypropyl) -N- (prop-2-enyl) - (R) -phenylglycine, 3,5bis (trifluoromethyl) benzyl acetal and N- (2- (R) -hydroxypropyl) -N - (prop-2-enyl) - (S) phenylglycine, 3,5-bis (trifluoromethyl) benzyl acetal

Zmes 933 mg (1,40 mmol) N-(2-(R)-hidroksi-propil)-fenilglicinala, 3,5-bis(trifluorometil)-benzil acetala (iz primera 19), 1 ml alil bromida, 600 mg (4,3 mmol) kalijevega karbonata in 5 ml etanola mešamo 20 ur pri 60 °C. Zmes ohladimo, porazdelimo med 100 ml etil etra in 25 ml vode in plasti ločimo. Flash kromatografija na 50 g silikagela, pri čemer uporabimo 20 : 1 v/v eter/heksane kot eluent, da 380 mg (R,R)-amino alkohola (Rf = 0,72 s 3 : 2 v/v eter/heksani kot eluentom), 220 mg (R,S)-amino alkohola (Rf = 0,62 s 3 : 2 v/v eter/heksani kot eluentom), in 285 mg zmesi diastereomernih amino alkoholov.A mixture of 933 mg (1.40 mmol) of N- (2- (R) -hydroxy-propyl) -phenylglycinal, 3,5-bis (trifluoromethyl) -benzyl acetal (from Example 19), 1 ml of allyl bromide, 600 mg ( 4.3 mmol) of potassium carbonate and 5 ml of ethanol were stirred for 20 hours at 60 ° C. The mixture was cooled, partitioned between 100 ml of ethyl ether and 25 ml of water and the layers separated. Flash chromatography on 50 g silica gel using 20: 1 v / v ether / hexanes as eluent to give 380 mg of (R, R) -amino alcohol (R f = 0.72 with 3: 2 v / v ether / hexanes) as eluent), 220 mg (R, S) -amino alcohol (R f = 0.62 with 3: 2 v / v ether / hexanes as eluent), and 285 mg of a mixture of diastereomeric amino alcohols.

Za (R,R)-amino alkohol:For (R, R) -amino alcohol:

Masni spekter (FAB): m/Z 704 (M+H).Mass spectrum (FAB): m / Z 704 (M + H).

IR (čist) 3476,2932,1624,1454,1361,1278,1175,1132, 760, 704,682.IR (pure) 3476,2932,1624,1454,1361,1278,1175,1132, 760, 704,682.

NMR (CDC13, 400 MHz, ppm) 1,12 (d, 3 H, J = 6,4), 2,19 in 2,62 (dAB q, 2 H, J ab = 13,0, J219 = 2,3, J 2>62 = 10,4), 2,97 (dd, 1 H, J = 14,0, 8,8), 3,25 - 3,30 (m, 1 H), 3,76 (s, 1 H), 3,77 - 3,85 (m, 1 H), 4,21 (d, 1 H, J = 8,8), 4,49 in 4,55 (AB q, 2 H, J = 12,4), 4,86 in 4,92 (AB q, 2 H, J = 12,4), 5,27 - 5,33 (m, 2 H), 5,39 (d, 1 H, J = 8,8), 5,79 - 5,89 (m, 1 H), 7,21 - 7,26 (m, 4 H), 7,35 - 7,40 (m, 3 H), 7,67 (s, 1 H), 7,81 (s, 1 H), 7,85 (s, 2 H).NMR (CDCl 3 , 400 MHz, ppm) 1.12 (d, 3 H, J = 6.4), 2.19 and 2.62 (dAB q, 2 H, J ab = 13.0, J 219 = 2.3, J 2> 62 = 10.4), 2.97 (dd, 1 H, J = 14.0, 8.8), 3.25 - 3.30 (m, 1 H), 3. 76 (s, 1 H), 3.77 - 3.85 (m, 1 H), 4.21 (d, 1 H, J = 8.8), 4.49 and 4.55 (AB q, 2 H, J = 12.4), 4.86 and 4.92 (AB q, 2 H, J = 12.4), 5.27-5.33 (m, 2 H), 5.39 (d, 1 H, J = 8.8), 5.79 - 5.89 (m, 1 H), 7.21 - 7.26 (m, 4 H), 7.35 - 7.40 (m, 3 H) ), 7.67 (s, 1H), 7.81 (s, 1H), 7.85 (s, 2H).

Analiza za C^H^F^NO^ izrač. C 54,63 H 4,15 N 1,99 F 32,41 ugot. C 54,72 H 3,94 N 1,95 F 32,17Analysis for C ^ H ^ F ^ NO ^ calc. C 54.63 H 4.15 N 1.99 F 32.41 found. C 54.72 H 3.94 N 1.95 F 32.17

Za (R.S)-amino alkohol:For (R.S) -amino alcohol:

Masni spekter (FAB): m/Z 704 (M+l).Mass spectrum (FAB): m / Z 704 (M + 1).

IR (čist) 3451,2931,1624,1454,1362,1277, 704,683.IR (pure) 3451,2931,1624,1454,1362,1277, 704,683.

XH NMR (CDC13, 400 MHz, ppm) 1,09 (d, 3 H, J = 6,0), 2,48 in 2,71 (dAB q, 2 H, J ab = 13,2, J 248 = 9,6, J 2 62 = 3,6), 3,05 (dd, 1 H, J = 14,4, 6,8), 3,34 - 3,39 (m, 1 H), 3,35 (s, 1 H), 3,76 - 3,81 (m, 1 H), 4,21 (d, 1 H, J = 8,4), 4,50 in 4,54 (AB q, 2 H, J = 12,8), 4,86 in 4,96 (AB q, 2 H J = 12,4), 5,10 - 5,17 (m, 2 H), 5,39 (d, 1 H, J = 8,4), 5,68 - 5,78 (m, 1 H), 7,23 - 7,32 (m, 4 H), 7,34 - 7,39 (m, 3 H), 7,69 (s, 1 H), 7,83 (s, 1 H), 7,86 (s, 2 H). X H NMR (CDCl 3 , 400 MHz, ppm) 1.09 (d, 3 H, J = 6.0), 2.48 and 2.71 (dAB q, 2 H, J ab = 13.2, J 248 = 9.6, J 2 62 = 3.6), 3.05 (dd, 1 H, J = 14.4, 6.8), 3.34 - 3.39 (m, 1 H), 3 , 35 (s, 1 H), 3.76 - 3.81 (m, 1 H), 4.21 (d, 1 H, J = 8.4), 4.50 and 4.54 (AB q, 2 H, J = 12.8), 4.86 and 4.96 (AB q, 2 HJ = 12.4), 5.10-5.17 (m, 2 H), 5.39 (d, 1 H, J = 8.4), 5.68 - 5.78 (m, 1 H), 7.23 - 7.32 (m, 4 H), 7.34 - 7.39 (m, 3 H) , 7.69 (s, 1H), 7.83 (s, 1H), 7.86 (s, 2H).

Analiza za C32H29F12NO3:Analysis for C 32 H 29 F 12 NO 3 :

izrač. C 54,63 H 4,15 N 1,99 F 32,41 ugot. C 54,80 H 4,16 N 1,90 F 32,36calcd. C 54.63 H 4.15 N 1.99 F 32.41 found. C 54.80 H 4.16 N 1.90 F 32.36

PRIMER 22EXAMPLE 22

N-(2-(S)-hidroksipropil)-N-(prop-2-enil)-(S)-fenilglicinah 3,5-bis(trifluorometil)benzil acetal in N-f2-fS)-hidroksipropil)-N-(prop-2-enin-fR)-fenil-glicinat 3,5bis(trifluorometii)benzil acetalN- (2- (S) -hydroxypropyl) -N- (prop-2-enyl) - (S) -phenylglycine 3,5-bis (trifluoromethyl) benzyl acetal and N-f2-fS) -hydroxypropyl) -N- (prop-2-enin-fR) -phenyl-glycinate 3,5bis (trifluoromethyl) benzyl acetal

S substitucijo 880 mg (1,33 mmol) N-(2-(S)-hidroksipropil)-fenilglicinala, 3,5bis(trifluorometil)benzil acetala (primer 20) z N-(2-(R)-hidroksipropil)-fenilglicinal, 3,5-bis(trifluorometil)benzil acetalom v postopkih predhodnega primera dobimo 281 mg (S,S)-amino alkohola (Rf = 0,72 s 3 : 2 v/v eter/heksani kot eluentom), 367 mg (S,R)-amino alkohola (Rf = 0,62 z 3 : 2 v/v eter/heksani kot eluentom) in 197 mg zmesi diastereomernih amino alkoholov.Substituting 880 mg (1.33 mmol) of N- (2- (S) -hydroxypropyl) -phenylglycine, 3,5bis (trifluoromethyl) benzyl acetal (example 20) with N- (2- (R) -hydroxypropyl) -phenylglycine , 3,5-bis (trifluoromethyl) benzyl acetal in the foregoing procedures afforded 281 mg (S, S) -amino alcohol (R f = 0.72 with 3: 2 v / v ether / hexanes as eluent), 367 mg ( Of the S, R) -amino alcohol (R f = 0.62 with 3: 2 v / v ether / hexanes as eluent) and 197 mg of a mixture of diastereomeric amino alcohols.

PRIMER 23EXAMPLE 23

2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-6-(R)-metil morfolin in 2-(S)(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-6-(R)-metil morfolin2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-6- (R) -methyl morpholine and 2- (S) (3,5-bis (trifluoromethyl) benzyloxy ) -3- (R) -phenyl-6- (R) -methyl morpholine

Korak A 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-4-(2-propenil)-6(R)-metil morfolin in 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)fenil-4-(2-propenil)-6-(R)-metil morfolinStep A 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-4- (2-propenyl) -6 (R) -methyl morpholine and 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) phenyl-4- (2-propenyl) -6- (R) -methyl morpholine

Raztopino 355 mg (0,50 mmol) N-(2-(R)-hidroksipropil)-N-(2-propenil)-(R)fenilglicinala, 3,5-bis(trifluorometil)benzil acetala (iz primera 21) in 285 mg (1,5 mmol) monohidrata p-toluensulfonske kisline v 5 ml toluena segrevamo 40 min. pri refluksu. Raztopino ohladimo in porazdelimo med 40 ml etra in 15 ml nasičene vodne raztopine natrijevega bikarbonata. Plasti ločimo; organsko plast speremo z 10ml nasičene vodne raztopine natrijevega klorida, posušimo preko magnezijevega sulfata in koncentriramo v vakuumu. Flash kromatografija na 10 g silikagela, pri čemer uporabimo 19 : 1 v/v heksani/eter kot eluent, da 122 mg (2R,3R,6R) produkta (Rf = 0,53 s 4 :1 v/v heksani/eter kot eluentom) in 62 mg (2S,3R,6R) produkta (Rf = 0,23 s 4 :1 v/v heksani/eter kot eluentom.A solution of 355 mg (0.50 mmol) of N- (2- (R) -hydroxypropyl) -N- (2-propenyl) - (R) phenylglycinal, 3,5-bis (trifluoromethyl) benzyl acetal (from Example 21), and 285 mg (1.5 mmol) of p-toluenesulfonic acid monohydrate in 5 ml of toluene was heated for 40 min. at reflux. The solution was cooled and partitioned between 40 ml of ether and 15 ml of saturated aqueous sodium bicarbonate solution. The layers are separated; The organic layer was washed with 10 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 10 g of silica gel using 19: 1 v / v hexanes / ether as eluant to give 122 mg (2R, 3R, 6R) of the product (R f = 0.53 with 4: 1 v / v hexanes / ether) as eluent) and 62 mg (2S, 3R, 6R) of the product (R f = 0.23 with 4: 1 v / v hexanes / ether as eluent).

Za (2R.3R.6R) produkt:For (2R.3R.6R) Product:

Masni spekter (FAB): m/Z 460 (M+H, 65 %)Mass Spectrum (FAB): m / Z 460 (M + H, 65%)

Ή NMR (CDC13, 430 MHz, ppm) 1,35 (d, 3 H, J = 6,4), 2,53 in 2,63 (dAB q, 2 H, J ab = 12,0, J 2 53 = 3,2, J 2>63 = 6,8), 2,83 - 2,96 (m, 2 H), 3,60 (d, 1 H, J = 4,0), 4,27 4,32 (m, 1 H),’ 4,57 in 4,84 (AB q, 2 H, J = 13,2), 4,87 (d, 1 H, J = 4,0), 5,08 - 5,13 (m,Ή NMR (CDCl 3 , 430 MHz, ppm) 1.35 (d, 3 H, J = 6.4), 2.53 and 2.63 (dAB q, 2 H, J ab = 12.0, J 2) 53 = 3.2, J 2> 63 = 6.8), 2.83 - 2.96 (m, 2 H), 3.60 (d, 1 H, J = 4.0), 4.27 4 , 32 (m, 1 H), '4.57 and 4.84 (AB q, 2 H, J = 13.2), 4.87 (d, 1 H, J = 4.0), 5.08 - 5.13 (m,

Η), 5,76 - 5,86 (m, 1 Η), 7,31 - 7,37 (m, 3 Η), 7,50 - 7,52 (m, 2 Η), 7,58 (s, 2 Η), 7,71 (s, IH).Η), 5.76 - 5.86 (m, 1 Η), 7.31 - 7.37 (m, 3 Η), 7.50 - 7.52 (m, 2 Η), 7.58 (s , 2 Η), 7.71 (s, 1H).

Za (2S.3R.6R) produkt:For the (2S.3R.6R) product:

Masni spekter (FAB): m/Z 460 (M+H, 65 %) XH NMR (CDC13, 400 MHz, ppm) 1,37 (d, 3 H, J = 6,8), 2,48 - 2,50 (m, 2 H), 2,74 in 3,01 (dtAB q, 2 H, J = 6,4,1,2,12,4) 3,84 (d, 1 H, J = 3,6), 3,92 - 3,99 (m, 1 H), 4,70 in 4,93 (AB q, 2 H, J = 13,6), 4,97 (d, 1 H, J = 3,6), 5,08 - 5,14 (m, 2 H), 5,74 - 5,84 (m, 1 H), 7,28 - 7,36 (m, 3 H), 7,43 - 7,46 (m, 2 H), 7,64 (s, 2 H), 7,75 (s, 1 H).Mass spectrum (FAB): m / Z 460 (M + H, 65%) X H NMR (CDCl 3 , 400 MHz, ppm) 1.37 (d, 3 H, J = 6.8), 2.48 - 2.50 (m, 2 H), 2.74 and 3.01 (dtAB q, 2 H, J = 6,4,1,2,12,4) 3,84 (d, 1 H, J = 3 , 6), 3.92 - 3.99 (m, 1 H), 4.70 and 4.93 (AB q, 2 H, J = 13.6), 4.97 (d, 1 H, J = 3.6), 5.08 - 5.14 (m, 2 H), 5.74 - 5.84 (m, 1 H), 7.28 - 7.36 (m, 3 H), 7.43 - 7.46 (m, 2 H), 7.64 (s, 2 H), 7.75 (s, 1 H).

Korak B 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-6-(R)-metil morfolinStep B 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-6- (R) -methyl morpholine

Raztopino 115 mg (0,25 mmol) 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil4-(2-propenil)-6-(R)-metil morfolina (iz primera 23, korak A) in 230 mg (0,25 mmol) tris(trifenilfosfin)rodijevega klorida v 15 ml 4 : 1 v/v acetonitrilu/vodi segrevamo 30 min. pri refluksu. Reakcijsko zmes ohladimo in porazdelimo med 50 ml etil acetata in 15 ml vode. Plasti ločimo in organsko plast posušimo preko magnezijevega sulfata. Vodno plast ekstrahiramo z 2 x 25 ml etil acetata; ekstrakte posušimo in združimo s prvotno organsko plastjo. Združene organske faze koncentriramo v vakuumu. Ostanek filtriramo preko blazinice silikagela (~ 20 g), pri čemer uporabimo 2 : 1 v/v eter/heksani kot topilo. Filtrat koncentriramo; flash kromatografija na 5 g silikagela, pri čemer uporabimo 17 : 3 v/v heksane/eter kot eluent, da 67 mg (64 %) 2-(R)-(3,5bis(trifluorometil)benziloksi)-3-(R)-fenil-6-(R)-metil morfolin kot olje.A solution of 115 mg (0.25 mmol) of 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl 4- (2-propenyl) -6- (R) -methyl morpholine ( from Example 23, step A) and 230 mg (0.25 mmol) of tris (triphenylphosphine) rhodium chloride in 15 ml of 4: 1 in / in acetonitrile / water was heated for 30 min. at reflux. The reaction mixture was cooled and partitioned between 50 ml of ethyl acetate and 15 ml of water. The layers were separated and the organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 2 x 25 ml ethyl acetate; the extracts are dried and combined with the original organic layer. The combined organic phases were concentrated in vacuo. The residue was filtered through a pad of silica gel (~ 20 g), using 2: 1 v / v ether / hexanes as solvent. The filtrate was concentrated; flash chromatography on 5 g silica gel using 17: 3 v / v hexanes / ether as eluant to give 67 mg (64%) of 2- (R) - (3,5bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-6- (R) -methyl morpholine as an oil.

Masni spekter (FAB): m/Z 420 (M+H, 90 %) *H NMR (CDC13, 400 MHz, ppm) 1,21 (d, 3 H, J = 6,4), 2,02 (širok s, 1 H), 2,67 in 2,77 (dAB q, 2 H, J = 13,2, J 2 67 = 8,8, J 277 = 3,2), 3,89 (d, 1 H, J = 2,4), 4,07 4,15 (m, 1 H), 4,68 in 4,90 (AB q, 2 H, J = 12,8), 5,03 (d, 1 H, J = 2,4), 7,28 - 7,38 (m,Mass spectrum (FAB): m / Z 420 (M + H, 90%) * H NMR (CDCl 3 , 400 MHz, ppm) 1.21 (d, 3 H, J = 6.4), 2.02 ( broad s, 1 H), 2.67 and 2.77 (dAB q, 2 H, J = 13.2, J 2 67 = 8.8, J 277 = 3.2), 3.89 (d, 1 H, J = 2.4), 4.07 4.15 (m, 1 H), 4.68 and 4.90 (AB q, 2 H, J = 12.8), 5.03 (d, 1 H, J = 2.4), 7.28-7.38 (m,

H), 7,51 - 7,53 (m, 2 H), 7,77 (s, 2 H), 7,79 (s, 1 H).H), 7.51 - 7.53 (m, 2 H), 7.77 (s, 2 H), 7.79 (s, 1 H).

Korak C 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-6-(R)-metil morfolinStep C 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-6- (R) -methyl morpholine

Izvedemo podobno reakcijo z uporabo 55 mg (0,12 mmol) 2-(S)-(3,5-bis(trifluorometil)-benziloksi)-3-(R)-fenil-4-(2-propenil)-6-(R)-metil morfolina (iz primera 23, korak A) in 111 mg (0,12 mmol) tris(trifenilfosfin)rodijevega klorida v 12 ml 4 : 1 v/v acetonitrila/vode. Flash kromatografija na 4 g silikagela, pri čemer uporabimo 50 : 1 v/v metilen klorid/acetonitril kot eluent, da 14 mg (28 %) 2-(S)78 (3,5-bis(trifluorometil)-benziloksi)-3-(R)-fenil-6-(R)-metil morfolin kot olje.A similar reaction was carried out using 55 mg (0.12 mmol) of 2- (S) - (3,5-bis (trifluoromethyl) -benzyloxy) -3- (R) -phenyl-4- (2-propenyl) -6- (R) -methyl morpholine (from Example 23, Step A) and 111 mg (0.12 mmol) of tris (triphenylphosphine) rhodium chloride in 12 ml of 4: 1 v / v acetonitrile / water. Flash chromatography on 4 g silica gel using 50: 1 v / v methylene chloride / acetonitrile as eluent to give 14 mg (28%) of 2- (S) 78 (3,5-bis (trifluoromethyl) -benzyloxy) -3 - (R) -phenyl-6- (R) -methyl morpholine as an oil.

Masni spekter (FAB): m/Z 420 (M+H, 90 %) XH NMR (CDC13, 400 MHz, ppm) 1,39 (d, 3 H, J = 6,8), 1,92 (širok s, 1 H), 2,84 in 2,95 (dAB q, 2 H, J AB = 12,8, J 284 = 6,4, J295 = 3,6), 3,93 - 4,00 (m, 1 H), 4,07 (d, 1 H, J = 2,8), 4,68 in 4,95 (AB q, 2 H, J = 13,2), 4,93 (d, 1 H, J = 2,8), 7,28 - 7,37 (m, 3 H), 7,48 - 7,52 (m, 2 H), 7,55 (s, 2 H), 7,72 (s, 1 H).Mass spectrum (FAB): m / Z 420 (M + H, 90%) X H NMR (CDCl 3 , 400 MHz, ppm) 1.39 (d, 3 H, J = 6.8), 1.92 ( wide s, 1 H), 2.84 and 2.95 (dAB q, 2 H, J AB = 12.8, J 284 = 6.4, J 295 = 3.6), 3.93 - 4.00 (m, 1 H), 4.07 (d, 1 H, J = 2.8), 4.68 and 4.95 (AB q, 2 H, J = 13.2), 4.93 (d, 1 H, J = 2.8), 7.28 - 7.37 (m, 3 H), 7.48 - 7.52 (m, 2 H), 7.55 (s, 2 H), 7. 72 (s, 1H).

PRIMER 24EXAMPLE 24

2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-6-(S)-metil morfolin in 2-(R)(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-6-(S)-metil morfolin2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-6- (S) -methyl morpholine and 2- (R) (3,5-bis (trifluoromethyl) benzyloxy ) -3- (S) -phenyl-6- (S) -methyl morpholine

S substitucijo 350 mg N-(2-(S)-hidroksipropil)-N-(2-propenil)-(S)-fenilglicinal, 3,5bis(trifluorometil)benzil acetala (iz primera 22) s N-(2-(R)-hidroksipropil)-N-(2propenil)-(R)-fenilglicinal, 3,5-bis(trifluorometil)benzil acetalom v poizkusu podobnem predhodnemu primeru, da 50 mg 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3(S)-fenil-6-(S)-metil morfolina in 14 mg 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3(S)-fenil-6-(S)-metil morfolina.Substituting 350 mg of N- (2- (S) -hydroxypropyl) -N- (2-propenyl) - (S) -phenylglycine, 3,5bis (trifluoromethyl) benzyl acetal (from Example 22) with N- (2- ( R) -hydroxypropyl) -N- (2-propenyl) - (R) -phenylglycine, 3,5-bis (trifluoromethyl) benzyl acetal in an experiment similar to the preceding example, that 50 mg of 2- (S) - (3,5-bis ( trifluoromethyl) benzyloxy) -3 (S) -phenyl-6- (S) -methyl morpholine and 14 mg of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3 (S) -phenyl-6- (S) -methyl morpholine.

PRIMER 25EXAMPLE 25

2-(R)-(3.5-bis(trifluorometil)benziloksi)-3-(S)-fenil-6-(R)-metil morfolin in 2-(S)~ (3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-6-(R)-metil morfolin2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-6- (R) -methyl morpholine and 2- (S) ~ (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-6- (R) -methyl morpholine

Korak A 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-4-(2-propenil)-6(R)-metil morfolin in 2-(S)-(3,5-bis(trifluorometil)-benziloksi)-3-(S)fenil-4-(2-propenil)-6-(R)-metil morfolinStep A 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-4- (2-propenyl) -6 (R) -methyl morpholine and 2- (S) - (3,5-bis (trifluoromethyl) -benzyloxy) -3- (S) phenyl-4- (2-propenyl) -6- (R) -methyl morpholine

Naslovni spojini pripravimo na način podoben primeru 23, korak A. Kristalizacijo 300 mg (0,43 mmol) N-(2-(R)-hidroksipropil)-N-(prop-2-enil)-(S)-fenilglicinal, 3,5bis(trifluorometil)-benzil acetala (iz primera 23) izvedemo z uporabo 246 mg (1,29 mmol) monohidrata p-toluensulfonske kisline in 5 ml toluena. Flash kromatografija na 8 g silikagela, pri čemer uporabimo 20 : 1 v/v heksani/eter kot eluent, da 149 mg (75 %) produktov kot neločljive diastereomere.The title compounds were prepared in a manner similar to Example 23, Step A. Crystallization of 300 mg (0.43 mmol) of N- (2- (R) -hydroxypropyl) -N- (prop-2-enyl) - (S) -phenylglycin, 3 , 5bis (trifluoromethyl) -benzyl acetal (from Example 23) was performed using 246 mg (1.29 mmol) of p-toluenesulfonic acid monohydrate and 5 ml of toluene. Flash chromatography on 8 g of silica gel using 20: 1 v / v hexanes / ether as eluant to give 149 mg (75%) of the product as inseparable diastereomers.

Masni spekter (FAB): m/Z 460 (M+H, 65 %).Mass spectrum (FAB): m / Z 460 (M + H, 65%).

Korak B _ 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-6-(S)-metil morfolin in 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-6-(R)metilmorfolinStep B - 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-6- (S) -methyl morpholine and 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-6- (R) methylmorpholine

Raztopino 150 mg (0,33 mmol) 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil4-(2-propenil)-6-(R)-metil morfolina in 2-(S)-(3,5-bis(trifluorometil)-benziloksi)-3(S)-fenil-4-(2-propenil)-6-(R)-metil morfolina (iz primera 25, korak A) in 318 mg (0,32 mmol) tris(trifenilfosfin)-rodijevega klorida v 20 ml 4 : 1 v/v acetonitrila/vode segrevamo 1 h pri refluksu. Flash kromatografija na 5 g silikagela, pri čemer uporabimo 9 : 1 v/v heksani/eter kot eluent, da 35 mg produktov kot zmesi in 26 mg 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-6-(R)-metil morfolina (Rf = 0,22 s 3 : 2 v/v heksani/eter kot eluentom. Kromatografija zmesi na 5 g silikagela, pri čemer uporabimo 20 : 1 v/v, da 14 mg 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)fenil-6-(R)-metil morfolina (Rf = 0,14 s 3 : 2 v/v heksani/eter kot eluentom) in 17 mg 2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-6-(R)-metil morfolina (41 % celokupni dobitek).A solution of 150 mg (0.33 mmol) of 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl 4- (2-propenyl) -6- (R) -methyl morpholine and 2- (S) - (3,5-bis (trifluoromethyl) -benzyloxy) -3 (S) -phenyl-4- (2-propenyl) -6- (R) -methyl morpholine (from Example 25, step A) and 318 mg (0.32 mmol) of tris (triphenylphosphine) rhodium chloride in 20 ml of 4: 1 v / v acetonitrile / water was heated at reflux for 1 h. Flash chromatography on 5 g of silica gel using 9: 1 v / v hexanes / ether as eluant to give 35 mg of the product as a mixture and 26 mg of 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3 - (S) -phenyl-6- (R) -methyl morpholine (R f = 0.22 with 3: 2 v / v hexanes / ether as eluent) Chromatography of the mixture on 5 g of silica gel using 20: 1 in / v, that 14 mg of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) phenyl-6- (R) -methyl morpholine (R f = 0.14 s 3: 2 v / in hexanes / ether as eluent) and 17 mg 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-6- (R) -methyl morpholine (41% overall yield) ).

Za (2R,3S,6R) produkt:For (2R, 3S, 6R) product:

Masni spekter (FAB): m/Z 420 (M+H, 90 %)Mass Spectrum (FAB): m / Z 420 (M + H, 90%)

Ή NMR (CDC13, 400 MHz, ppm) 1,30 (d, 3 H, J = 6,4), 1,74 (širok s, 1 H), 2,73 in 2,98 (dAB q, 2 H, J = 11,6, J 273 = 10,0, J 298 = 2,4), 3,65 (d, 1 H, J = 7,2), 3,89 3,94 (m, 1 H), 4,45 (d, 1 H, J = 7,2), 4,53 in 4,90 (AB q, 2 H, J = 13,2), 7,28 - 7,38 (m, 3 H), 7,41 - 7,43 (m, 2 H), 7,45 (s, 2 H), 7,70 (s, 1 H).Ή NMR (CDCl 3 , 400 MHz, ppm) 1.30 (d, 3 H, J = 6.4), 1.74 (broad s, 1 H), 2.73 and 2.98 (dAB q, 2 H, J = 11.6, J 273 = 10.0, J 298 = 2.4), 3.65 (d, 1 H, J = 7.2), 3.89 3.94 (m, 1 H) ), 4.45 (d, 1 H, J = 7.2), 4.53 and 4.90 (AB q, 2 H, J = 13.2), 7.28 - 7.38 (m, 3) H), 7.41 - 7.43 (m, 2 H), 7.45 (s, 2 H), 7.70 (s, 1 H).

Za (2S,3S,6R) produkt:For (2S, 3S, 6R) product:

Masni spekter (FAB): m/Z 420 (M+H, 90 %) ]H NMR (CDC13, 400 MHz, ppm) 1,20 (d, 3 H, J = 6,4), 2,04 (širok s, 1 H), 2,84 inMass spectrum (FAB): m / Z 420 (M + H, 90%) ] H NMR (CDCl 3 , 400 MHz, ppm) 1.20 (d, 3 H, J = 6.4), 2.04 ( wide s, 1 H), 2.84 in

3.15 (dAB q, 2 H, J = 12,8, J 2 84 = 10,8, J 315 = 2,8), 4,08 (d, 1 H, J = 2,8), 4,08 4.15 (m, 1 H), 4,53 in 4,80 (AB q, 2 H, J = 13,2), 4,79 (d, 1 H, J = 2,8), 7,28 - 7,38 (m, 5 H), 7,43 (s, 2H), 7,70 (s, IH).3.15 (dAB q, 2 H, J = 12.8, J 2 84 = 10.8, J 315 = 2.8), 4.08 (d, 1 H, J = 2.8), 4.08 4.15 (m, 1 H), 4.53 and 4.80 (AB q, 2 H, J = 13.2), 4.79 (d, 1 H, J = 2.8), 7.28 - 7, 38 (m, 5H), 7.43 (s, 2H), 7.70 (s, 1H).

PRIMER 26EXAMPLE 26

2- (Sl-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-6-(S)-metil morfolin in 2-(R)(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-6-(S)-metil morfolin2- (Sl- (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-6- (S) -methyl morpholine and 2- (R) (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-6- (S) -methyl morpholine

S substitucijo 250 mg N-(2-(S)-hidroksi-propil)-N-(2-propenil)-(S)-fenilglicinala, 3,5bis-(trifluorometil)benzil acetala (iz primera 22) z N-(2-(R)-hidroksipropil)-N-(2propenil)-(R)-fenil-glicinal, 3,5-bis(trifluorometil)benzil acetalom v poizkusu podobnem predhodnemu primeru dobimo 42 mg 2-(S)-(3,5-bis(trifluorometil)benziloksi)3- (R)-fenil-6-(S)-metil morfolina in 17 mg 2-(S)-(3,5-bis(trifluorometil)benziloksi)3-(R)-fenil-6-(S)-metil morfolina.Substituting 250 mg of N- (2- (S) -hydroxy-propyl) -N- (2-propenyl) - (S) -phenylglycinol, 3,5bis- (trifluoromethyl) benzyl acetal (from Example 22) with N- ( 2- (R) -hydroxypropyl) -N- (2-propenyl) - (R) -phenyl-glycine, 3,5-bis (trifluoromethyl) benzyl acetal, in an experiment similar to the preceding example, 42 mg of 2- (S) - (3, 5-bis (trifluoromethyl) benzyloxy) 3- (R) -phenyl-6- (S) -methyl morpholine and 17 mg of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) 3- (R) - phenyl-6- (S) -methyl morpholine.

PRIMER 27EXAMPLE 27

2-(R)-(3'5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(R)-metil morfolin, 2-(S)-(3,5bis-(trifluorometil)benziloksi)-3-(S)-fenil-5-(R)-metil morfolin, 2-R ali S)-(3,5bis(trifluorometil)-benziloksi)-3-(R)-fenil-5-(R)-metilmorfolin in 2-(S ali R)-(3,5bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(R)-metilmorfolin2- (R) - (3'5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (R) -methyl morpholine, 2- (S) - (3,5bis- (trifluoromethyl) benzyloxy ) -3- (S) -phenyl-5- (R) -methyl morpholine, 2-R or S) - (3,5bis (trifluoromethyl) -benzyloxy) -3- (R) -phenyl-5- (R) -methylmorpholine and 2- (S or R) - (3,5bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-5- (R) -methylmorpholine

Izvedba sekvence, ki je opisana v primeru 19, pri čemer substituiramo (R)-l-amino2-propanol z (R)-2-amino-l-propanolom zagotovi zmes 55 mg materiala z visokim Rf in 56 mg materiala z nizkim Rf Material z visokim Rf pridobimo po primeru 23, korak A zgoraj, da zagotovimo 10 mg materiala z visokim Rf (2-(R)-(3,5bis(trifluorometil)benziloksi)-3-(S)-fenil-l-5-(R)-metil morfolina in 7 mg materiala z nizkim Rf (2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(R)-metil morfolina. Material z nizkim Rf (po tem, ko smo ga združili z dodatnimi 30 mg materiala) pridobimo po primeru 23, korak A, da zagotovimo 24 mg materiala z visokim Rf (2(R ali S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(R)-metil-morfolina in 18 mg materiala z nizkim Rf (2-(S ali R)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil5-(R)-metilmorfolina.The embodiment of the sequence described in Example 19, wherein substituted (R) -1-amino2-propanol with (R) -2-amino-1-propanol provides a mixture of 55 mg of high R f material and 56 mg of low R material f The material with high R f is obtained from Example 23, step A above, to provide 10 mg of material with high R f (2- (R) - (3,5bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-l 5- (R) -methyl morpholine and 7 mg of a material of low R f (2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (R) - A low R f material (after being combined with an additional 30 mg of material) is obtained from Example 23, Step A, to provide 24 mg of a high R f material (2 (R or S) - (3, 5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-5- (R) -methyl-morpholine and 18 mg of low R f (2- (S or R) - (3,5-bis ( trifluoromethyl) benzyloxy) -3- (R) -phenyl5- (R) -methylmorpholine.

2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(R)-metil morfolin Masni spekter (FAB): m/Z 420 (M+H, 100 %), 227 (50 %), 192 (75 %), 176 (65 %). NMR (CDC13, 400 MHz, ppm): δ 0,98 (d, 3 H, J = 6,3 Hz), 3,16 - 3,20 (m, 1 H), 3,43 - 3,47 (m, 1 H), 3,79 (d, 1 H), J = 7,5 Hz), 3,91 ( dd, 1 H, J = 3,2 & 11,5 Hz), 4,51 (d, 2 H, J = 13,4 Hz), 4,85 (d, 1 H, J = 13,2 Hz), 7,29 -7,45 (m, 7 H), 7,67 (s, 1 H).2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (R) -methyl morpholine Mass spectrum (FAB): m / Z 420 (M + H, 100 %), 227 (50%), 192 (75%), 176 (65%). NMR (CDCl 3 , 400 MHz, ppm): δ 0.98 (d, 3 H, J = 6.3 Hz), 3.16 - 3.20 (m, 1 H), 3.43 - 3.47 (m, 1 H), 3.79 (d, 1 H), J = 7.5 Hz), 3.91 (dd, 1 H, J = 3.2 & 11.5 Hz), 4.51 ( d, 2 H, J = 13.4 Hz), 4.85 (d, 1 H, J = 13.2 Hz), 7.29 -7.45 (m, 7 H), 7.67 (s. 1 H).

2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(R)-metil morfolin2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (R) -methyl morpholine

Masni spekter (FAB): m/Z 420 (M+H, 48 %), 227 (35 %), 192 (39 %), 176 (100 %).Mass spectrum (FAB): m / Z 420 (M + H, 48%), 227 (35%), 192 (39%), 176 (100%).

NMR (CDC13, 400 MHz, ppm): δ 1,10 (d, 3 H, J = 6,4 Hz), 3,23 - 3,26 (m, 1 H), 3,56NMR (CDCl 3 , 400 MHz, ppm): δ 1.10 (d, 3 H, J = 6.4 Hz), 3.23 - 3.26 (m, 1 H), 3.56

- 3,61 (m, 2 H), 4,17 (d, 1 H, J = 2,3 Hz), 4,51 (d, 1 H, J = 13,7 Hz), 4,71 (d, 1 H, J =- 3.61 (m, 2 H), 4.17 (d, 1 H, J = 2.3 Hz), 4.51 (d, 1 H, J = 13.7 Hz), 4.71 (d , 1 H, J =

2,4 Hz), 4,78 (d, 1 H, J = 13,5 Hz), 7,28 - 7,39 (m, 7 H), 7,68 (s, 1 H).2.4 Hz), 4.78 (d, 1 H, J = 13.5 Hz), 7.28-7.39 (m, 7 H), 7.68 (s, 1 H).

2-(R ali S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(R)-metil morfolin2- (R or S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-5- (R) -methyl morpholine

Masni spekter (FAB): m/Z 281 (35 %), 221 (55 %), 207 (45 %), 192 (40 %), 147 (100 %).Mass spectrum (FAB): m / Z 281 (35%), 221 (55%), 207 (45%), 192 (40%), 147 (100%).

NMR (CDC13, 400 MHz, ppm): δ 1,13 (d, 3 H, J = 6,6 Hz), 3,10 - 3,14 (m, 1 H), 3,66 (dd, 1 H, J = 6,6 & 11,4 Hz), 3,76 (dd, 1 H, J = 3,5 & 11,2 Hz), 4,04 (d, 1 H, J = 4,0 Hz), 4,61 (d, 1 H, J = 13,2 Hz), 4,74 (d, 1 H, J = 3,9 Hz), 4,89 (d, 1 H, 13,2 Hz), 7,26 7,35 (m, 3 H), 7,47 - 7,49 (m, 2 H); 7,64 (s, 1 H), 7,74 (s, 1 H).NMR (CDCl 3 , 400 MHz, ppm): δ 1.13 (d, 3 H, J = 6.6 Hz), 3.10 - 3.14 (m, 1 H), 3.66 (dd, 1 H, J = 6.6 & 11.4 Hz), 3.76 (dd, 1 H, J = 3.5 & 11.2 Hz), 4.04 (d, 1 H, J = 4.0 Hz) ), 4.61 (d, 1 H, J = 13.2 Hz), 4.74 (d, 1 H, J = 3.9 Hz), 4.89 (d, 1 H, 13.2 Hz) , 7.26 7.35 (m, 3 H), 7.47 - 7.49 (m, 2 H); 7.64 (s, 1H), 7.74 (s, 1H).

2-(R ali S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(R)-metil morfolin2- (R or S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-5- (R) -methyl morpholine

NMR (CDC13, 400 MHz, ppm): d 1,36 (d, 3 H, J = 6,7 Hz), 3,27 - 3,31 (m, 1 H), 3,39 (dd, 1 H, J = 2,2 & 11,3 Hz), 4,16 (dd, 1 H, J = 3,2 & 11,0 Hz), 4,37 (d, 1 H, J = 2,3 Hz), 4,53 (d, 1 H, J = 13,5 Hz), 4,75 (d, 1 H, J = 2,5 Hz), 4,81 (d, 1 H, 13,6 Hz), 7,26NMR (CDCl 3 , 400 MHz, ppm): d 1.36 (d, 3 H, J = 6.7 Hz), 3.27-3.31 (m, 1 H), 3.39 (dd, 1 H, J = 2.2 & 11.3 Hz), 4.16 (dd, 1 H, J = 3.2 & 11.0 Hz), 4.37 (d, 1 H, J = 2.3 Hz) ), 4.53 (d, 1 H, J = 13.5 Hz), 4.75 (d, 1 H, J = 2.5 Hz), 4.81 (d, 1 H, 13.6 Hz) , 7.26

- 7,35 (m, 3 H), 7,26 - 7,43 (m, 7 H), 7,68 (s, 1 H).- 7.35 (m, 3 H), 7.26 - 7.43 (m, 7 H), 7.68 (s, 1 H).

PRIMER 28EXAMPLE 28

2-(R ali S)-(3,5-bis(trifluorometil)-benziloksi)-3-(S)-fenil-5-(S)-metilmorfolin, 2-(S ali2- (R or S) - (3,5-bis (trifluoromethyl) -benzyloxy) -3- (S) -phenyl-5- (S) -methylmorpholine, 2- (S or

R)-(3,5-(-bis-(trifluorometil)benziloksi)-3-(S)-fenil-5-(S)-metil morfolin in 2-(R)(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(S)-metilmorfolinR) - (3,5 - (- bis- (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (S) -methyl morpholine and 2- (R) (3,5-bis (trifluoromethyl) benzyloxy ) -3- (R) -phenyl-5- (S) -methylmorpholine

Izvedba sekvence, ki je opisana v primeru 19, s substitucijo (R)-l-amino-2-propanola s (S)-2-amino-l-propanolom zagotovi zmes 78 mg materiala z visokim Rf in 70 mg materiala z nizkim Rf Material z visokim Rf pridobimo po primeru 23, korak A zgoraj, da zagotovimo manj kot 1 mg materiala z visokim Rf 2-(R)(3,5)bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(S)-metilmorfolina) in 9 mg materiala z nizkim Rf (2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(S)-metil morfolina. Material z nizkim Rf pridobimo po primeru 23, korak A, da zagotovimo 20 mg materiala z visokim Rf (2-(R ali S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5(S)-metilmorfolina in 14 mg materiala z nizkim Rf (2-(S ali R)-(3,5bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(S)-metilmorfolina.The embodiment of the sequence described in Example 19 by substituting (R) -1-amino-2-propanol with (S) -2-amino-1-propanol provides a mixture of 78 mg of high R f material and 70 mg of low R f The material with high R f is obtained from Example 23, step A above, to provide less than 1 mg of material with high R f 2- (R) (3,5) bis (trifluoromethyl) benzyloxy) -3- (S) - phenyl-5- (S) -methylmorpholine) and 9 mg of low R f (2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (S) material The low R f material is obtained from Example 23, Step A, to provide 20 mg of the high R f material (2- (R or S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- ( S) -phenyl-5 (S) -methylmorpholine and 14 mg of low R f (2- (S or R) - (3,5bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (S) material ) -methylmorpholine.

2-(R ali S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(S)-metil morfolin2- (R or S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (S) -methyl morpholine

Masni spekter (FAB): m/Z 420 (M+H, 60 %), 227 (68 %), 192 (56 %), 176 (100 %). NMR (CDC13, 400 MHz, ppm): δ 1,12 (d, 3 H, J = 6,6 Hz), 3,09 - 3,14 (m, 1 H), 3,65 (dd, 1 H, J = 6,6 & 11,0 Hz), 3,75 (dd, 1 H, J = 3,6 & 11,1 Hz), 4,04 (d, 1 H, J = 3,9 Hz), 4,61 (d, 1 H, J = 13,2 Hz), 4,73 (d, 1 H, J = 3,9 Hz), 4,89 (d, 1 H, 13,2 Hz), 7,28 7,35 (m, 3 H), 7,47 (d, 2 H, 7,0 Hz), 7,64 (s, 1 H) 7,74 (s, 1 H).Mass spectrum (FAB): m / Z 420 (M + H, 60%), 227 (68%), 192 (56%), 176 (100%). NMR (CDCl 3 , 400 MHz, ppm): δ 1.12 (d, 3 H, J = 6.6 Hz), 3.09 - 3.14 (m, 1 H), 3.65 (dd, 1 H, J = 6.6 & 11.0 Hz), 3.75 (dd, 1 H, J = 3.6 & 11.1 Hz), 4.04 (d, 1 H, J = 3.9 Hz) ), 4.61 (d, 1 H, J = 13.2 Hz), 4.73 (d, 1 H, J = 3.9 Hz), 4.89 (d, 1 H, 13.2 Hz) , 7.28 7.35 (m, 3 H), 7.47 (d, 2 H, 7.0 Hz), 7.64 (s, 1 H) 7.74 (s, 1 H).

2-(S ali R)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(S)-metil morfolin2- (S or R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (S) -methyl morpholine

Masni spekter (FAB): m/Z 420 (M+H, 50 %), 227 (45 %), 192 (40 %), 176 (100 %). NMR (CDC13, 400 MHz, ppm): δ 1,36 (d, 3 H, J = 6,9 Hz), 3,27 - 3,29 (m, 1 H), 3,39 (dd, 1 H, J = 2,2 & 11,1 Hz), 4,15 (dd, 1 H, J = 3,3 & 11,1 Hz), 4,37 (d, 1 H, J = 2,5 Hz), 4,52 (d, 1 H, J = 13,3 Hz), 4,75 (d, 1 H, J = 2,4 Hz), 4,81 (d, 1 H, 13,5 Hz), 7,28 7,43 (m, 7 H), 7,68 (s, 1 H).Mass spectrum (FAB): m / Z 420 (M + H, 50%), 227 (45%), 192 (40%), 176 (100%). NMR (CDCl 3 , 400 MHz, ppm): δ 1.36 (d, 3 H, J = 6.9 Hz), 3.27-3.29 (m, 1 H), 3.39 (dd, 1 H, J = 2.2 & 11.1 Hz), 4.15 (dd, 1 H, J = 3.3 & 11.1 Hz), 4.37 (d, 1 H, J = 2.5 Hz) ), 4.52 (d, 1 H, J = 13.3 Hz), 4.75 (d, 1 H, J = 2.4 Hz), 4.81 (d, 1 H, 13.5 Hz) , 7.28 7.43 (m, 7H), 7.68 (s, 1H).

2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(S)-metil morfolin NMR (CDC13, 400 MHz, ppm): δ 1,10 (d, 3 H, J = 6,4 Hz), 3,22 - 3,25 (m, 1 H), 3,55 - 3,60 (m, 2 H), 4,17 (d, 1 H, J = 2,3 Hz), 4,51 (d, 1 H, J = 13,5 Hz), 4,71 (d, 1 H, J =2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-5- (S) -methyl morpholine NMR (CDCl 3 , 400 MHz, ppm): δ 1.10 ( d, 3 H, J = 6.4 Hz), 3.22 - 3.25 (m, 1 H), 3.55 - 3.60 (m, 2 H), 4.17 (d, 1 H, d). J = 2.3 Hz), 4.51 (d, 1 H, J = 13.5 Hz), 4.71 (d, 1 H, J =

2,4 Hz), 4,77 (d, 1 H, J = 13,6 Hz), 7,28 - 7,38 (m, 7 H), 7,67 (s, 1 H).2.4 Hz), 4.77 (d, 1 H, J = 13.6 Hz), 7.28-7.38 (m, 7 H), 7.67 (s, 1 H).

PRIMER 29EXAMPLE 29

2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(R)-fenilmorfolin, 2-S)-(3,5bis(trifluorometil)benziloksi)-3-fS)-fenil-5-(R)-fenil-morfolin in 2-(R ali S)-(3,5bis(trifluorometil)-benziloksi)-3-(R)-fenil-5-(R)-fenilmorfolin2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (R) -phenylmorpholine, 2-S) - (3,5bis (trifluoromethyl) benzyloxy) -3 -fS) -phenyl-5- (R) -phenyl-morpholine and 2- (R or S) - (3,5bis (trifluoromethyl) -benzyloxy) -3- (R) -phenyl-5- (R) -phenylmorpholine

Izvedba sekvence, kije opisana v primeru 19, s substitucijo (R)-l-amino-2-propanola z (R)-2-amino-2-feniletanolom zagotovi zmes 62 mg materiala z visokim Rf in 52 mg materiala z nizkim Rf Material z visokim Rf pridobimo po primeru 23, korak A zgoraj, da zagotovimo 16 mg materiala z visokom Rf (2-(R)-(3,5bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(R)-fenilmorfolina in 4 mg materiala z nizkim Rf (2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(R)-fenilmorfolina. Material z nizkim Rf pridobimo po primeru 23, korak A, da zagotovimo 4 mg produkta (2-(R ali S)-(3,5-bis(trifluorometil)benzil-oksi)-3-(R)-fenil-5-(R)fenilmorfolina.The embodiment of the sequence described in Example 19 by substituting (R) -1-amino-2-propanol with (R) -2-amino-2-phenylethanol provides a mixture of 62 mg of high R f material and 52 mg of low R material f The material with high R f is obtained from Example 23, step A above, to provide 16 mg of material with high R f (2- (R) - (3,5bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5 - (R) -phenylmorpholine and 4 mg of low R f (2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (R) -phenylmorpholine material. low R f is obtained from Example 23, Step A, to provide 4 mg of the product (2- (R or S) - (3,5-bis (trifluoromethyl) benzyl-oxy) -3- (R) -phenyl-5- (R) phenylmorpholine.

2-(R)-(3,5-bis(trifluorometiObenziloksi)-3-(S)-feniI-5-fR)-fenilmorfolin2- (R) - (3,5-bis (trifluoromethylbenzyloxy) -3- (S) -phenyl-5-fluoro-phenylmorpholine

NMR (CDC13, 400 MHz, ppm): δ 3,62 (t, 1 H, J = 10,7 & 21,5 Hz), 3,93 (d, 1 H, J =NMR (CDCl 3 , 400 MHz, ppm): δ 3.62 (t, 1 H, J = 10.7 & 21.5 Hz), 3.93 (d, 1 H, J =

7,4 Hz), 3,99 (dd, 1 H, J = 3,1 & 11,2 Hz), 4,18 (dd, 1 H, J = 3,0 & 10,2 Hz), 4,46 (d, 1 H, J = 7,4 Hz), 4,53 (d, 1 H, J = 13,5 Hz), 4,89 (d, 1 H, J = 13,3 Hz), 7,28 - 7,55 (m, 12H), 7,69(s, IH).7.4 Hz), 3.99 (dd, 1 H, J = 3.1 & 11.2 Hz), 4.18 (dd, 1 H, J = 3.0 & 10.2 Hz), 4. 46 (d, 1 H, J = 7.4 Hz), 4.53 (d, 1 H, J = 13.5 Hz), 4.89 (d, 1 H, J = 13.3 Hz), 7 , 28-7.55 (m, 12H), 7.69 (s, 1H).

2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(R)-fenilmorfolin2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (R) -phenylmorpholine

NMR (CDC13, 400 MHz, ppm): δ 3,67 (dd, 1 H, J = 3,5 & 11,0 Hz), 3,89 (d, 1 H, J = 10,8 & 21,6 Hz), 4,25 (dd, 1 H, J = 3,3 & 11,0 Hz), 4,34 (d, 1 H, J = 2,2 Hz), 4,52 (d, 1 H, J = 13,8 Hz), 4,78 - 4,87 (m, 2 H), 7,28 - 7,51 (m, 12 H), 7,69 (s, 1 H).NMR (CDCl 3 , 400 MHz, ppm): δ 3.67 (dd, 1 H, J = 3.5 & 11.0 Hz), 3.89 (d, 1 H, J = 10.8 &21; 6 Hz), 4.25 (dd, 1 H, J = 3.3 & 11.0 Hz), 4.34 (d, 1 H, J = 2.2 Hz), 4.52 (d, 1 H) , J = 13.8 Hz), 4.78 - 4.87 (m, 2 H), 7.28 - 7.51 (m, 12 H), 7.69 (s, 1 H).

2-(R ali S)-(3.5-bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(R)-fenilmorfolin NMR (CDC13, 400 MHz, ppm): δ 4,10 - 4,25 (m, 2 H), 4,30 - 4,38 (m, 1 H), 4,48 4,54 (m, 1 H), 4,59 - 4,66 (m, 1 H), 4,86 - 5,00 (m, 2 H), 7,25 - 7,74 (m, 13 H).2- (R or S) - (3.5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-5- (R) -phenylmorpholine NMR (CDCl 3 , 400 MHz, ppm): δ 4.10 - 4 , 25 (m, 2 H), 4.30 - 4.38 (m, 1 H), 4.48 4.54 (m, 1 H), 4.59 - 4.66 (m, 1 H), 4.86 - 5.00 (m, 2 H), 7.25 - 7.74 (m, 13 H).

PRIMER 30EXAMPLE 30

2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(S)-fenilmorfolin, 2-(R)-(3,5bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(S)-fenilmorfolin, 2-(R ali S)-(3,5-bis(trifluorometil)-benziloksi)-3-(S)-fenil-5-(S)-fenil-morfolin in 2-(R ali S)-(3,5bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(S)-fenilmorfolin2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-5- (S) -phenylmorpholine, 2- (R) - (3,5bis (trifluoromethyl) benzyloxy) - 3- (R) -phenyl-5- (S) -phenylmorpholine, 2- (R or S) - (3,5-bis (trifluoromethyl) -benzyloxy) -3- (S) -phenyl-5- (S) -phenyl-morpholine and 2- (R or S) - (3,5bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (S) -phenylmorpholine

Izvedba sekvence, ki je opisana v primeru 19, s substitucijo (R)-l-amino-2-propanola s (S)-2-amino-2-feniletanolom zagotovi zmes 75 mg materiala z visokim Rf in 64 mg materiala z nizkim Rf Material z visokim Rf pridobimo po primeru 23, korak A zgoraj, da zagotovimo 23 mg materiala z visokim Rf (2-(S)-(3,5bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(S)-fenilmorfolina [L-740, 930] in 7 mg materiala z nizkim Rf (2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(S)fenilmorfolina. Material z nizkim Rf pridobimo po primeru 23, korak A, da zagotovimo 26 mg materiala z višjim Rf (2-(R ali S)-(3,5bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(S)-fenilmorfolina in 6 mg materiala z nižjim Rf (2-(R ali S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(S)fenilmorfolina.The embodiment of the sequence described in Example 19 by substituting (R) -1-amino-2-propanol with (S) -2-amino-2-phenylethanol provides a mixture of 75 mg of high R f material and 64 mg of low R f The material with high R f is obtained from Example 23, step A above, to provide 23 mg of material with high R f (2- (S) - (3,5bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl- 5- (S) -phenylmorpholine [L-740, 930] and 7 mg of low R f (2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-5 material - (S) phenylmorpholine The material with low R f is obtained from Example 23, step A to provide 26 mg of material with higher R f (2- (R or S) - (3,5bis (trifluoromethyl) benzyloxy) -3- ( S) -phenyl-5- (S) -phenylmorpholine and 6 mg of material with lower R f (2- (R or S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5 - (S) Phenylmorpholine.

2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(S)-fenilmorfolin2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-5- (S) -phenylmorpholine

NMR (CDC13, 400 MHz, ppm): δ 3,60 - 3,74 (m, 1 H), 3,94 (d, 1 H, J = 7,6 Hz), 4,00 (dd, 1 H, J = 3,2 & 11,3 Hz), 4,18 - 4,21 (m, 1 H), 4,50 - 4,55 (m, 2 H), 4,89 (m, 1 H),NMR (CDCl 3 , 400 MHz, ppm): δ 3.60 - 3.74 (m, 1 H), 3.94 (d, 1 H, J = 7.6 Hz), 4.00 (dd, 1 H, J = 3.2 & 11.3 Hz), 4.18 - 4.21 (m, 1 H), 4.50 - 4.55 (m, 2 H), 4.89 (m, 1 H) ),

7.26 - 7,55 (m, 12 H), 7,69 (s, 1 H).7.26 - 7.55 (m, 12 H), 7.69 (s, 1 H).

2-(R)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil-5-(S)-fenilmorfolin2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl-5- (S) -phenylmorpholine

NMR (CDC13, 400 MHz, ppm): δ 3,68 (dd, 1 H, J = 3,0 & 11,0 Hz), 3,88 - 3,94 (m, 1 H), 4,26 - 4,30 (m, 1 H), 4,36 (s, 1 H), 4,52 (d, 1 H, J = 13,5 Hz), 4,77 - 4,86 (m, 2 H),NMR (CDCl 3 , 400 MHz, ppm): δ 3.68 (dd, 1 H, J = 3.0 & 11.0 Hz), 3.88 - 3.94 (m, 1 H), 4.26 - 4.30 (m, 1 H), 4.36 (s, 1 H), 4.52 (d, 1 H, J = 13.5 Hz), 4.77 - 4.86 (m, 2 H) ),

7.27 - 7,51 (m, 12 H), 7,69 (s, 1 H).7.27 - 7.51 (m, 12 H), 7.69 (s, 1 H).

2-(R ali S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(S)-fenilmorfolin NMR (CDC13, 400 MHz, ppm): δ 3,93 - 3,95 (m, 1 H), 4,06 - 4,21 (m, 2 H), 4,38 - 4,42 (m, 1 H), 4,59 - 4,68 (m, 2 H), 4,83 - 4,94 (m, 2 H), 7,25 - 7, 81 (m, 13 H).2- (R or S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (S) -phenylmorpholine NMR (CDCl 3 , 400 MHz, ppm): δ 3.93 - 3.95 (m, 1 H), 4.06 - 4.21 (m, 2 H), 4.38 - 4.42 (m, 1 H), 4.59 - 4.68 (m, 2 H), 4.83 - 4.94 (m, 2 H), 7.25 - 7, 81 (m, 13 H).

2-(R ali S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-5-(Sj-fenilmorfolin NMR (CDC13, 400 MHz, ppm): δ 3,43 - 3,59 (m, 2 H), 3,82 (d, 1 H, J = 7,2 Hz), 4,25 (d, 1 H, J = 12,5 Hz), 4,52 - 4,63 (m, 3 H), 4,80 - 4,90 (širok s, 1 H), 7,11 - 7,81 (m, 13 H)·2- (R or S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-5- (S 1 -phenylmorpholine NMR (CDCl 3 , 400 MHz, ppm): δ 3.43 - 3.59 (m, 2 H), 3.82 (d, 1 H, J = 7.2 Hz), 4.25 (d, 1 H, J = 12.5 Hz), 4.52 - 4. 63 (m, 3 H), 4.80 - 4.90 (broad s, 1 H), 7.11 - 7.81 (m, 13 H) ·

PRIMER 31EXAMPLE 31

2-(S)-(3,5-bis(trifluorometil)benziloksi)-6-fR)-metil-3-(S)-fenil-4-f3-fl,2,4-triazolo)metil)-morfolin2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -6-fluoro-methyl-3- (S) -phenyl-4-fluoro, 2,4-triazolo) methyl) -morpholine

Po postopku podanem v primeru 17, korak B, da 98 mg (0,24 mmol) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-6-(R)-metil morfolina (iz primera 25 zgoraj), 38 mg (0,28 mmol) N-formil-2-kloroacetamidrazona (iz primera 17, korak A zgoraj) in 97 mg (0,7 mmol) brezvodnega kalijevega karbonata, po flash kromatografiji na 28 g kremenice, pri čemer eluiramo z 1 1 100 : 4 : 0,5 metilen klorid: metanol :amoniakalna voda, rahlo rumeno trdno snov, ki po prekristalizaciji iz heksanov/metilen klorida zgotovi 77 mg (66 %) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-6-(R)-metil-3-(S)-fenil-4-(3-(l,2,4-triazolo)metil)-morfolina kot bel prah.Following the procedure given in Example 17, Step B, 98 mg (0.24 mmol) of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-6- (R) -methyl-morpholine (from Example 25 above), 38 mg (0.28 mmol) of N-formyl-2-chloroacetamidrazone (from Example 17, step A above) and 97 mg (0.7 mmol) of anhydrous potassium carbonate, by flash chromatography per 28 g of quartz, eluting with 1 1 100: 4: 0,5 methylene chloride: methanol: ammoniacal water, a slightly yellow solid, which after recrystallisation from hexanes / methylene chloride yields 77 mg (66%) of 2- (S ) - (3,5-bis (trifluoromethyl) benzyloxy) -6- (R) -methyl-3- (S) -phenyl-4- (3- (1,2,4-triazolo) methyl) -morpholine as white dust.

NMR (CDC13, 400 MHz, ppm): δ 1,17 (d, J = 6,3, 3 H), 2,29 (t, J = 11,1, 1 H), 2,92 (d, J = 11,1, 1 H), 3,42 (d, J = 15,3,1 H), 3,58 (s, 1 H), 3,88 (d, J = 15,4 1 H), 4,20 4,33 (m, 1 H), 4,43 (d, 13,5,1 H), 4,71 (d, J = 2,4,1 H), 4,74 (d, J = 13,3,1 H), 7,30 7,55 (m, 7 H),7,69 (s, 1 H), 7,95 (s, 1 H).NMR (CDCl 3 , 400 MHz, ppm): δ 1.17 (d, J = 6.3, 3 H), 2.29 (t, J = 11.1, 1 H), 2.92 (d. J = 11.1, 1 H), 3.42 (d, J = 15.3.1 H), 3.58 (s, 1 H), 3.88 (d, J = 15.4 1 H) , 4.20 4.33 (m, 1H), 4.43 (d, 13.5.1 H), 4.71 (d, J = 2.4.1 H), 4.74 (d, J = 13.3.1 H), 7.30 7.55 (m, 7 H), 7.69 (s, 1 H), 7.95 (s, 1 H).

PRIMER 32EXAMPLE 32

2-(s)-(3,5-bis(trifluorometil)benziloksi)-6-(R)-metil-4-(3-(5-okso-lH,4H-l,2,4-triazolo)metil)-3-(S)-fenilmorfolin2- (s) - (3,5-bis (trifluoromethyl) benzyloxy) -6- (R) -methyl-4- (3- (5-oxo-1H, 4H-1,2,4-triazolo) methyl) -3- (S) -phenylmorpholine

Zmes 96 mg (0,23 mmol) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenil-6-(R)metil morfolina (iz primera 25 zgoraj), 46 mg (0,28 mmol) N-metilkarboksi-2kloroacetamidrazona in 95 mg (0,69 mmol) brezvodnega kalijevega karbonata v 3 ml suhega DMF mešamo 20 min. pri sobni temperatturi, pri 60 °C 90 min. in nato 2 h pri 120 °C. Zmes ohladimo na sobno temperaturo, prevzamemo v 15 ml etil acetata in speremo s 3 x 10 ml vode. Združene vodne plasti povratno ekstrahiramo z 10 ml etil acetata, združene organske plasti speremo z 10 ml slanice, posušimo preko natrijevega sulfata, filtriramo in koncentriramo v vakuumu. Ostanek prečistimo s falsh kromatografijo na 28 g kremenice, pri čemer eluiramo z 1 1 100 : 4 metilen klorid:metanol, da dobimo 65 mg (55 %) 2-(S)-(3,5-bis(trifluorometil)benziloksi)6-(R)-metil-4-(3-(5-okso-lH,4H-l,2,4-triazolo)-metil)-3-(S)-fenilmorfolina kot rahlo rumen prah.Mixture of 96 mg (0.23 mmol) 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenyl-6- (R) methyl morpholine (from Example 25 above), 46 mg (0.28 mmol) of N-methylcarboxy-2chloroacetamidrazone and 95 mg (0.69 mmol) of anhydrous potassium carbonate in 3 ml of dry DMF were stirred for 20 min. at room temperature, at 60 ° C for 90 min. and then at 120 ° C for 2 h. The mixture was cooled to room temperature, taken up in 15 ml of ethyl acetate and washed with 3 x 10 ml of water. The combined aqueous layers were back extracted with 10 ml of ethyl acetate, the combined organic layers were washed with 10 ml of brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on 28 g of silica eluting with 1 1 100: 4 methylene chloride: methanol to give 65 mg (55%) of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) 6 - (R) -methyl-4- (3- (5-oxo-1H, 4H-1,2,4-triazolo) -methyl) -3- (S) -phenylmorpholine as a slightly yellow powder.

NMR (CDC13, 400 MHz, ppm): δ 1,18 (d, J = 6,2, 3 H), 2,15 (t, J = 11,1, 1 H), 2,89 (d, J = 14, 2 H), 3,49 (d, J = 2,2,1 H), 3,61 (d, J = 14,4,1 H), 4,20 - 4,30 (m, 1 H), 4,45 (d, J = 13,6,1 H), 4,67 (d, J = 2,5,1 H), 4,79 (d, J = 13,5,1 H), 7,25 - 7,50 (m, 7 H), 7,62 (s, 1 H), 10,07 (s, 1 H), 10,35 (s, 1 H).NMR (CDCl 3 , 400 MHz, ppm): δ 1.18 (d, J = 6.2, 3 H), 2.15 (t, J = 11.1, 1 H), 2.89 (d. J = 14, 2 H), 3.49 (d, J = 2.2.1 H), 3.61 (d, J = 14.4.1 H), 4.20 - 4.30 (m, 1 H), 4.45 (d, J = 13.6.1 H), 4.67 (d, J = 2.5.1 H), 4.79 (d, J = 13.5.1 H) ), 7.25 - 7.50 (m, 7 H), 7.62 (s, 1 H), 10.07 (s, 1 H), 10.35 (s, 1 H).

PRIMER 33EXAMPLE 33

2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenil morfolin2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenyl morpholine

Korak A 4-benzil-2-(S)-hidroksi-3-(R)-fenilmorfolinStep A 4-Benzyl-2- (S) -hydroxy-3- (R) -phenylmorpholine

Raztopino 3,72 g (13,9 mmol) 4-benzil-3-(R)-fenil-2-morfolinona, pripravljenega iz (R)-fenilglicina, kot je opisano v primeru 14, v 28 ml CH2C12 ohladimo v -78 °C kopeli pod N2 atmosfero in dodamo 14 ml 1,5 M raztopine DIBAL-H (21 mmol) v toluenu. Po mešanju nastale raztopine 0,5 h, pustimo, da se segreje na -50 °C in jo vzdržujemo pri tej temperaturi 0,5 h. Reakcijsko zmes pogasimo z dodatkom 10 ml vodnega kalijevega natrijevega tartrata. Zmes razredčimo z CH2C12 in plasti ločimo. Vodno plast ekstrahiramo 3-krat s CF^C^. CH2C12 plasti speremo s slanico, posušimo preko Na2SO4 in filtriramo. Koncentracija filtrata nudi 3,32 g (88 %) 4-benzil-2-(S)-hidroksi-3-(R)-fenilmorfolina, primernega za uporabo v naslednjem koraku.A solution of 3.72 g (13.9 mmol) of 4-benzyl-3- (R) -phenyl-2-morpholinone prepared from (R) -phenylglycine, as described in Example 14, was cooled in 28 ml of CH 2 Cl 2 in a -78 ° C bath under N 2 atmosphere and 14 ml of 1.5 M DIBAL-H solution (21 mmol) in toluene are added. After stirring the resulting solution for 0.5 h, allow it to warm to -50 ° C and maintain it at this temperature for 0.5 h. The reaction mixture was quenched by the addition of 10 ml of aqueous potassium sodium tartrate. The mixture was diluted with CH 2 C1 2 and the layers were separated. The aqueous layer was extracted 3 times with CF2Cl2. The CH 2 C1 2 layers were washed with brine, dried over Na 2 SO 4 and filtered. The filtrate concentration provided 3.32 g (88%) of 4-benzyl-2- (S) -hydroxy-3- (R) -phenylmorpholine suitable for use in the next step.

NMR (CDC13) 2,28 (m, 1 H), 2,71 (m, 1 H), 2,91 (d, J = 13 Hz, 1 H), 3,09 (d, J = 6 Hz, 1 H), 3,69 (d, J = 13 Hz, 1 H), 3,82 (td, J = 10 Hz in 2 Hz, 1 H), 3,91 (d, J = 10 Hz, 1 H), 4,73 (t, J = 6 Hz, 1 H), 7,2 - 7,52 (m, 10 H).NMR (CDCl 3 ) 2.28 (m, 1 H), 2.71 (m, 1 H), 2.91 (d, J = 13 Hz, 1 H), 3.09 (d, J = 6 Hz) , 1 H), 3.69 (d, J = 13 Hz, 1 H), 3.82 (td, J = 10 Hz and 2 Hz, 1 H), 3.91 (d, J = 10 Hz, 1 H), 4.73 (t, J = 6 Hz, 1 H), 7.2 - 7.52 (m, 10 H).

Korak B 4-benzil-2-(S)-(3,5-bis(trifluorometil)-benziloksi)-3-(R)-fenilmorfolinStep B 4-Benzyl-2- (S) - (3,5-bis (trifluoromethyl) -benzyloxy) -3- (R) -phenylmorpholine

K suspenziji 0,592 g (14,8 mmol) NaH v 30 ml suhega THF pri 0 °C dodamo 3,32 g (12,3 mmol) 4-benzil-2-(S)-hidroksi-3-(R)-fenilmorfolina pripravljenega v koraku A. Po 15 min. dodamo 0,915 g tetrabutilamonijevega jodida (2,47 mmol) in 2,4 ml (13 mmol) 3,5-bis(trifluorometil)benzil bromida. Nastalo zmes mešamo 1 h pri temperaturi ledene kopeli, nato vanjo zlijemo nasičeno raztopino NaHCO3 in ekstrahiramo z etil acetatom (EtOAc). Organske plasti združimo, speremo s slanico, posušimo preko Na2SO4 in filtriramo. Filtrat koncentriramo v vakuumu in ostanek kromatografiramo na Waters Prep500 HPLC sistemu, pri čemer uporabimo 50 % EtOAc/heksan, da izoliramo 3,6 g (59 %)4-benzil-2-(S)-(3,5bis(trilfuorometil)benziloksi)-3-(R)-fenilmorfolina.To a suspension of 0.592 g (14.8 mmol) of NaH in 30 ml of dry THF at 0 ° C was added 3.32 g (12.3 mmol) of 4-benzyl-2- (S) -hydroxy-3- (R) -phenylmorpholine prepared in step A. After 15 min. 0.915 g of tetrabutylammonium iodide (2.47 mmol) and 2.4 ml (13 mmol) of 3,5-bis (trifluoromethyl) benzyl bromide are added. The resulting mixture was stirred for 1 h at ice bath temperature, then a saturated NaHCO 3 solution was poured into it and extracted with ethyl acetate (EtOAc). The organic layers were combined, washed with brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed on a Waters Prep500 HPLC system using 50% EtOAc / hexane to isolate 3.6 g (59%) of 4-benzyl-2- (S) - (3,5bis (trifluoromethyl) benzyloxy ) -3- (R) -phenylmorpholine.

XH NMR (CDC13) 2,3 (td, J = 11 Hz in 3 Hz, 1 H), 2,71 (d, J = 11 Hz, 1 H), 2,90 (d, J = 13 Hz, 1 H), 3,22 (d, J = 7,3 Hz, 1 H), 3,75 (m, 2 H), 3,93 (m, 1 H), 4,43 (d, J = 13 Hz, 1 H), 4,45 (d, J = 7,3 Hz, 1 H), 4,82 (d, J = 13 Hz, 1 H), 7,19 - 7,5 (m, 12 H), 7,67 (s, IH). X H NMR (CDCl 3 ) 2.3 (td, J = 11 Hz and 3 Hz, 1 H), 2.71 (d, J = 11 Hz, 1 H), 2.90 (d, J = 13 Hz) , 1 H), 3.22 (d, J = 7.3 Hz, 1 H), 3.75 (m, 2 H), 3.93 (m, 1 H), 4.43 (d, J = 13 Hz, 1 H), 4.45 (d, J = 7.3 Hz, 1 H), 4.82 (d, J = 13 Hz, 1 H), 7.19 - 7.5 (m, 12 H), 7.67 (s, 1H).

Korak C 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenilmorfolinStep C 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenylmorpholine

Raztopino 3,6 g (7,27 mmol) 4-benzil-2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)fenilmorfolina v 100 ml etanola in 5 ml vode, ki vsebuje 0,72 g 10 % Pd/C hidrogeniramo na Parr-ovi aparaturi 36 h. Katalizator filtriramo in temeljito speremo z EtOAc. Filtrat koncentriramo in ostanek porazdelimo med vodo in EtOAc. EtOAc plast speremo s slanico, posušimo preko Na2SO4, filtriramo in koncentriramo. Ostanek prečistimo s flash kromatografijo, pri čemer uporabimo gradient 10 - 60 % EtOAc/heksan, da izoliramo 2,05 g (70 %) 2-(S)-(3,5-bis(trifluorometil)benziloksi)3-(R)-fenilmorfolina.A solution of 3.6 g (7.27 mmol) of 4-benzyl-2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) phenylmorpholine in 100 ml of ethanol and 5 ml of water containing 0.72 g of 10% Pd / C was hydrogenated on a Parr apparatus for 36 h. The catalyst was filtered and washed thoroughly with EtOAc. The filtrate was concentrated and the residue partitioned between water and EtOAc. The EtOAc layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash chromatography using a gradient of 10-60% EtOAc / hexane to isolate 2.05 g (70%) of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) 3- (R) -phenylmorpholine.

Ή NMR (CDC13) 1,92 (širok s, 1 H), 2,91 (m, 1 H), 3,05 (td, J = 11 Hz in 3 Hz, 1 H), 3,68 (d, J = 7 Hz, 1 H), 3,81 (td, J = 11 Hz in 3 Hz, 1 H), 4,01 (m, 1 H), 4,44 (d, J = 7 Hz), 4,5 (d, J = 13 Hz, 1 H), 4,85 (d, J = 13 Hz, 1 H), 7,28 - 7,42 (m, 7 H), 7,67 (s, 1 H)·Ή NMR (CDCl 3 ) 1.92 (broad s, 1 H), 2.91 (m, 1 H), 3.05 (td, J = 11 Hz and 3 Hz, 1 H), 3.68 (d , J = 7 Hz, 1 H), 3.81 (td, J = 11 Hz and 3 Hz, 1 H), 4.01 (m, 1 H), 4.44 (d, J = 7 Hz). 4.5 (d, J = 13 Hz, 1 H), 4.85 (d, J = 13 Hz, 1 H), 7.28 - 7.42 (m, 7 H), 7.67 (s, 1 H) ·

PRIMER 34EXAMPLE 34

4-(3-(1.2.4-triazolo)metil)-2-(S)-(3.5-bis(trifluorometil)benziloksi)-3-(R)-fenilmorfolin4- (3- (1,2,4-triazolo) methyl) -2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenylmorpholine

Naslovno spojino pripravimo s postopkom primera 17, korak B, pri čemer uporabimo produkt primera 33, korak C, kot izhodni material.The title compound was prepared by the procedure of Example 17, Step B, using the product of Example 33, Step C, as starting material.

XH NMR (CDC13) 1,75 (širok s, 1 H), 2,61 (td, J = 12 Hz in 2 Hz, 1 H), 2,83 (d, J = 12 Hz, 1 H), 3,33 (d, J = 7 Hz, 1 H), 3,48 (d, J = 15 Hz, 1 H), 3,78 (d, J = 15 Hz, 1 H), 3,85 (m, 1 H), 3,99 (m, 1 H), 4,44 (d, J = 13 Hz, 1 H), 4,49 (d, J = 7 Hz, 1 H), 4,81 (d, J = 13 Hz, 1 H), 7,23 - 7,45 (m, 7 H), 7,67 (s, 1 H), 7,96 (s, 1 H). X H NMR (CDCl 3 ) 1.75 (broad s, 1 H), 2.61 (td, J = 12 Hz and 2 Hz, 1 H), 2.83 (d, J = 12 Hz, 1 H) , 3.33 (d, J = 7 Hz, 1 H), 3.48 (d, J = 15 Hz, 1 H), 3.78 (d, J = 15 Hz, 1 H), 3.85 ( m, 1 H), 3.99 (m, 1 H), 4.44 (d, J = 13 Hz, 1 H), 4.49 (d, J = 7 Hz, 1 H), 4.81 ( d, J = 13 Hz, 1 H), 7.23 - 7.45 (m, 7 H), 7.67 (s, 1 H), 7.96 (s, 1 H).

PRIMER 35EXAMPLE 35

4-(3-(5-okso-lH,4H-1.2.4-triazolo)metil-2-(S)-(3.5-bis-(trifluorometilbenziloksi)-3(R)-fenilmorfolin4- (3- (5-oxo-1H, 4H-1,2,4-triazolo) methyl-2- (S) - (3,5-bis- (trifluoromethylbenzyloxy) -3 (R) -phenylmorpholine

Naslovno spojino pripravimo s postopkom primera 18, koraka B in C, pri čemer uporabimo produkt primera 33, korak C, kot izhodni material.The title compound was prepared by the procedure of Example 18, steps B and C, using the product of Example 33, step C, as starting material.

PRIMER 36EXAMPLE 36

4-(2-(imidazolo)metil)-2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenilmorfolin4- (2- (imidazolo) methyl) -2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenylmorpholine

Raztopino 101 mg (0,25 mmol) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)fenilmorfolina (primer 15), 98 mg (1,0 mmol) imidazol-2-karboksaldehida in 5 kapljic ledocetne kisline v 3 ml metanola obdelamo z 1,5 ml IM raztopine natrijevega cianoborohidrida v THF. Po 16 h, reakcijsko zmes pogasimo s 5 ml nasičene vodne raztopine natrijevega bikarbonata in porazdelimo med 40 ml etil acetata in 20 ml vode. Organsko plast ločimo, posušimo preko magnezijevega sulfata in koncentriramo v vakuumu. Flash kromatografija na 8 g silikagela, pri čemer uporabimo 50 : 1 : 0,1 metilen klorid/metanol/amonijev hidroksid kot eluent, da 54 mg (44 % dobitek) naslovne spojine kot belo trdno snov.A solution of 101 mg (0.25 mmol) of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) phenylmorpholine (Example 15), 98 mg (1.0 mmol) of imidazole-2- of carboxaldehyde and 5 drops of glacial acetic acid in 3 ml of methanol are treated with 1.5 ml of IM solution of sodium cyanoborohydride in THF. After 16 h, the reaction mixture was quenched with 5 ml of saturated aqueous sodium bicarbonate solution and partitioned between 40 ml of ethyl acetate and 20 ml of water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 8 g of silica gel using 50: 1: 0.1 methylene chloride / methanol / ammonium hydroxide as eluent to give 54 mg (44% yield) of the title compound as a white solid.

JH NMR (CDC13) 2,60 (dt, J = 3,2 Hz in 12,4 Hz, 1 H), 2,85 (d, J = 12,4 Hz, 1 H), 1 H NMR (CDCl 3 ) 2.60 (dt, J = 3.2 Hz and 12.4 Hz, 1 H), 2.85 (d, J = 12.4 Hz, 1 H),

3,28 (d, J = 14,4 Hz, IH), 3,59 (d, J = 2,8 H z, 1 H), 3,66 (dd, J = 2,0, 11,6 Hz, 1 H), 3,84 (d, J = 14,4 Hz, 1 H), 3,94 (jasen s, 2 H), 4,14 (dt, J = 2,0,12,0 Hz, 1 H), 4,43 (d,3.28 (d, J = 14.4 Hz, 1H), 3.59 (d, J = 2.8 H z, 1 H), 3.66 (dd, J = 2.0, 11.6 Hz) , 1 H), 3.84 (d, J = 14.4 Hz, 1 H), 3.94 (clear s, 2 H), 4.14 (dt, J = 2.0.12.0 Hz, 1 H), 4.43 (d,

J = 13,6 Hz, 1 H), 4,71 (d, J = 2,8 Hz, 1 H) 4,78 (d, J = 13,6 Hz, 1 H), 6,99 (jasen s,J = 13.6 Hz, 1 H), 4.71 (d, J = 2.8 Hz, 1 H) 4.78 (d, J = 13.6 Hz, 1 H), 6.99 (clear s ,

H), 7,25 - 7,48 (m, 6 H), 7,72 (s, 1 H).H), 7.25 - 7.48 (m, 6H), 7.72 (s, 1H).

Masni spekter (FAB): m/z 486 (100 %, M+H).Mass spectrum (FAB): m / z 486 (100%, M + H).

PRIMER 37EXAMPLE 37

4-(2-(imidazolo)metil)-2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenilmorfolin4- (2- (imidazolo) methyl) -2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenylmorpholine

Naslovno spojino pripravimo s postopkom primera 36, pri čemer uporabimo ustrezne izhodne materiale.The title compound was prepared according to the procedure of Example 36, using appropriate starting materials.

JH NMR (CDC13) 2,53 (td, J = 11 Hz in 3 Hz, 1 H), 2,74 (d, J = 12 Hz, 1 H), 3,23 (d, J = 7 Hz, 1 H), 3,32 (d, J = 15 Hz, 1 H), 3,66 (d, J = 15 Hz, 1 H), 3,77 (td, J = 11 Hz in 2 Hz, 1 H), 3,99 (m, 1 H), 4,44 (m, 2 H), 4,8 (d, J = 13 Hz, 1 H), 6,94 (s, 2 H), 7,2 7,45 (m, 7H), 7,67(s, IH). J H NMR (CDCl 3 ) 2.53 (td, J = 11 Hz and 3 Hz, 1 H), 2.74 (d, J = 12 Hz, 1 H), 3.23 (d, J = 7 Hz) , 1 H), 3.32 (d, J = 15 Hz, 1 H), 3.66 (d, J = 15 Hz, 1 H), 3.77 (td, J = 11 Hz and 2 Hz, 1 H), 3.99 (m, 1 H), 4.44 (m, 2 H), 4.8 (d, J = 13 Hz, 1 H), 6.94 (s, 2 H), 7. 2 7.45 (m, 7H), 7.67 (s, 1H).

PRIMER 38EXAMPLE 38

4-(5-(imidazolo)metil)-2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenilmorfolin4- (5- (imidazolo) methyl) -2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenylmorpholine

Naslovno spojino pripravimo s postopkom primera 36, pri čemer uporabimo ustrezne izhodne materiale.The title compound was prepared according to the procedure of Example 36, using appropriate starting materials.

*H NMR (CDC13) 2,47 (td, J = 12 Hz in 3 Hz, 1 H), 2,83 (d, J = 12 Hz, 1 H), 3,2 (m, 2 H), 3,61 (d, J = 14 Hz, 1 H), 3,79 (td, J = 12 Hz in 2 Hz, 1 H), 3,96 (m, 1 H), 4,44 (m, 2 H), 480 (d, J = 13 Hz, 1 H), 6,81 (s, 1 H), 7,28 - 7,45 (m, 7 H), 7,60 (s, 1 H), 7,66 (s, 1 H).1 H NMR (CDCl 3 ) 2.47 (td, J = 12 Hz and 3 Hz, 1 H), 2.83 (d, J = 12 Hz, 1 H), 3.2 (m, 2 H). 3.61 (d, J = 14 Hz, 1 H), 3.79 (td, J = 12 Hz and 2 Hz, 1 H), 3.96 (m, 1 H), 4.44 (m, 2 H), 480 (d, J = 13 Hz, 1 H), 6.81 (s, 1 H), 7.28 - 7.45 (m, 7 H), 7.60 (s, 1 H). 7.66 (s, 1H).

PRIMER 39EXAMPLE 39

4-(aminokarbonilmetil)-2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)-fenilmorfolin4- (aminocarbonylmethyl) -2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) -phenylmorpholine

Naslovno spojino pripravimo s postopkom primera 15, pri čemer uporabimo ustrezne izhodne materiale.The title compound was prepared by the procedure of Example 15, using appropriate starting materials.

Ή NMR (CDC13) 2,54 (td, J = 11 Hz in 2 Hz, 1 H), 2,64 (d, J = 17 Hz, 1 H), 2,93 (d, J = 12 Hz, 1 H), 3,14 (d, J = 17 Hz, 1 H), 3,27 (d, J = 7 Hz, 1 H), 3,83 (td, J = 11 Hz in 2 Hz, 1 H), 4,05 (m, 1 H), 4,46 (m, 2 H), 4,81 (d, J = 13 Hz, 1 H), 5,62 (širok s, 1 H), 6,80 (širok s, 1 H), 7,28 - 7,32 (m, 7 H), 7,67 (s, 1 H).Ή NMR (CDCl 3 ) 2.54 (td, J = 11 Hz and 2 Hz, 1 H), 2.64 (d, J = 17 Hz, 1 H), 2.93 (d, J = 12 Hz. 1 H), 3.14 (d, J = 17 Hz, 1 H), 3.27 (d, J = 7 Hz, 1 H), 3.83 (td, J = 11 Hz and 2 Hz, 1 H) ), 4.05 (m, 1 H), 4.46 (m, 2 H), 4.81 (d, J = 13 Hz, 1 H), 5.62 (broad s, 1 H), 6. 80 (broad s, 1H), 7.28-7.32 (m, 7H), 7.67 (s, 1H).

PRIMERI 40 do 43EXAMPLES 40 to 43

4-(3-(1,2,4-triazolo)metil)-2-(3-terc.-butil)-5-metilbenziloksi)-3-fenil-morfolin,4- (3- (1,2,4-triazolo) methyl) -2- (3-tert-butyl) -5-methylbenzyloxy) -3-phenyl-morpholine,

4-(3-(5-okso-lH,4H-l,2,4-triazolo)metil)-2-(3-terc.-butil)-5-metilbenziloksi)-3-fenilmorfolin, 4-(2-(imidazolo)metil)-2-(3-terc.-butil)-5-metilbenziloksi)-3-fenil-morfolin,4- (3- (5-oxo-1H, 4H-1,2,4-triazolo) methyl) -2- (3-tert-butyl) -5-methylbenzyloxy) -3-phenylmorpholine, 4- (2- (imidazolo) methyl) -2- (3-tert-butyl) -5-methylbenzyloxy) -3-phenyl-morpholine,

4-(4-(imidazolo)-metil)-2-(3-(terc.-butil)-5-metil-benziloksi)-3-fenil-morfolin4- (4- (imidazolo) -methyl) -2- (3- (tert-butyl) -5-methyl-benzyloxy) -3-phenyl-morpholine

Vsako od naslovnih spojin pripravimo s postopki primerov 15, 17 in 18, pri čemeruporabimo ustrezno substituirane izhodne materiale in reagente.Each of the title compounds is prepared by the procedures of Examples 15, 17 and 18 using suitably substituted starting materials and reagents.

PRIMER 44EXAMPLE 44

2-fSl-(3,5-diklorobenziloksi)-3-(S)-fenilmorfolin2-fluoro- (3,5-dichlorobenzyloxy) -3- (S) -phenylmorpholine

Korak A 3,5-diklorobenzil alkohol, trifluorometansulfonatni esterStep A 3,5-dichlorobenzyl alcohol, trifluoromethanesulfonate ester

Raztopino 6,09 g (34,4 mmol) 3,5-diklorobenzil alkohola in 8,48 g (41,3 mmol) 2,6di-t-butil-4-metilpiridina v 280 ml suhega ogljikovega tetraklorida pod atmosfero dušika obdelamo s 5,95 ml (35,4 mmol) trifluorometansulfonskim anhidridom pri sobni temperaturi. Bela oborina se tvori kmalu po dodajanju anhidrida. Po 90 min. suspenzijo filtriramo pod dušikom s Schlenk-ovim filtrom in filtrat koncentriramo v vakuumu. Ostanek, ki je dvo-fazno olje, raztopimo pod dušikom v 60 ml suhega toluena. Nastalo raztopino uporabimo neposredno v koraku B spodaj.A solution of 6.09 g (34.4 mmol) of 3,5-dichlorobenzyl alcohol and 8.48 g (41.3 mmol) of 2,6-di-t-butyl-4-methylpyridine in 280 ml of dry carbon tetrachloride under nitrogen atmosphere is treated with 5.95 ml (35.4 mmol) of trifluoromethanesulfonic anhydride at room temperature. A white precipitate forms shortly after the anhydride is added. After 90 min. the suspension was filtered under nitrogen with a Schlenk filter and the filtrate was concentrated in vacuo. The residue, which is a two-phase oil, is dissolved under nitrogen in 60 ml of dry toluene. Use the resulting solution directly in step B below.

Korak B: 4-benzil-2-(S)-(3,5-diklorobenziloksi)-3-(S)-fenilmorfolinStep B: 4-Benzyl-2- (S) - (3,5-dichlorobenzyloxy) -3- (S) -phenylmorpholine

Raztopino 5,11 g (19,1 mmol) N-benzil-3-(S)-fenilmorfolin-2-ona (iz primera 14) v 100 ml suhega THF ohladimo do -75 °C pod dušikom in obdelamo po kapljicah z 20,5 ml (20,5 mmol) IM raztopine litijevega tri(sek.-butil)-borohirida (LSelectride —) v THF. Po mešanju raztopine 30 min. pri - 75 °C, dodamo po cevki raztopino 3,5-diklorobenzil akohol, trifluorometansulfonatnega estra v toluenu (iz primera 44, korak A) tako, da notranjo temperaturo vzdržujemo pod -60 °C. Nastalo raztopino mešamo 9 h med -38 °C in -50 °C in jo nato obdelamo s 14 ml vodnega amoniaka in shranimo za 12 h pri -20 °C. Raztopine nato zlijemo v zmes 50 ml etil acetata in 100 ml vode, in plasti ločimo. Vodno fazo ekstrahiramo z 2 x 100 ml etil acetata, vsak ekstrakt speremo s slanico, združene organske plasti posušimo preko natrijevega sulfata, zmes filtriramo in filtrat koncentriramo v vakuumu. Ostanek prečistimo s flash kromatografijo na 235 g kremenice, pri čemer eluiramo z 1,5 1100 : 2 heksani:etil acetatom, nato 1,5 1100 : 3 heksani:etil acetatom in nato 1,9 1100 : 5 heksani:etil acetatom, da dobimo 4,4 g (54 %) olja, ki je po JH NMR 8 : 1 zmes cis:trans morfolinov.A solution of 5.11 g (19.1 mmol) of N-benzyl-3- (S) -phenylmorpholin-2-one (Example 14) in 100 ml of dry THF was cooled to -75 ° C under nitrogen and treated dropwise with 20 , 5 ml (20.5 mmol) of IM solution of lithium tri (sec-butyl) -borohydride (LSelectride -) in THF. After stirring the solution for 30 min. at - 75 ° C, a solution of 3,5-dichlorobenzyl ether, trifluoromethanesulfonate ester in toluene (from Example 44, step A) was added by tube, keeping the internal temperature below -60 ° C. The resulting solution was stirred for 9 h between -38 ° C and -50 ° C and then treated with 14 ml of aqueous ammonia and stored for 12 h at -20 ° C. The solutions were then poured into a mixture of 50 ml of ethyl acetate and 100 ml of water, and the layers were separated. The aqueous phase was extracted with 2 x 100 ml of ethyl acetate, each extract was washed with brine, the combined organic layers were dried over sodium sulfate, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on 235 g of silica eluting with 1.5 1100: 2 hexanes: ethyl acetate, then 1.5 1100: 3 hexanes: ethyl acetate and then 1.9 1100: 5 hexanes: ethyl acetate to give 4.4 g (54%) of the oil are obtained, which according to 1 H NMR is a 8: 1 mixture of cis: trans morpholines.

Masni spekter (FAB); m/Z 430, 428, 426 (M+H, -60 %), 268 (M-ArCH^ 100 %), 252 (M-ArCHjO, 75 %), 222 (20 %), 159 (45 %).Mass Spectrum (FAB); m / Z 430, 428, 426 (M + H, -60%), 268 (M-ArCH? 100%), 252 (M-ArCH? O, 75%), 222 (20%), 159 (45%).

*H NMR (CDC13, 400 MHz, ppm): δ glavni (cis) izomer: 2,32 (td, J = 12, 3,6, 1 H), 2,84 (jasen t, J = 13, 2 H), 3,52 (d, J = 2,6,1 H), 3,55 (dq, J = 11,3,1,6,1 H), 3,91 (d, J = 13,3, 1 H), 4,12 (td, J = 11,6, 2,4 1 H), 4,29 (d J = 13,6,1 H), 4,59 (d, J = 2,9, 1 H), 4,60 (d, J = 13,6), 6,70 (s, 2 H), 7,13 (t, J = 1,9, 1 H), 7,2 - 7,6 (m, 8 H), 7,53 (širok d, 2 H).1 H NMR (CDCl 3 , 400 MHz, ppm): δ major (cis) isomer: 2.32 (td, J = 12, 3.6, 1 H), 2.84 (clear t, J = 13, 2 H), 3.52 (d, J = 2.6.1 H), 3.55 (dq, J = 11.3.1,6.1 H), 3.91 (d, J = 13.3) , 1 H), 4.12 (td, J = 11.6, 2.4 1 H), 4.29 (d J = 13.6.1 H), 4.59 (d, J = 2.9 , 1 H), 4.60 (d, J = 13.6), 6.70 (s, 2 H), 7.13 (t, J = 1.9, 1 H), 7.2 - 7. 6 (m, 8 H), 7.53 (broad d, 2 H).

Korak C: 2-(S)-(3.5-diklorobenziloksi)-3-(S)-fenilmorfolinStep C: 2- (S) - (3,5-Dichlorobenzyloxy) -3- (S) -phenylmorpholine

Raztopino 0,33 g (0,77 mmol) 4-benzil-2-(S)-(3,5-diklorobenziloksi)-3-(S)-fenilmorfolina (iz primera 44, korak B) in 0,22 g (1,54 mmol) 1-kloroetil kloroformata v 4,5 ml 1,2-dikloroetana damo v tlačno posodo, ki jo potopimo v oljno kopel, ki jo segrevamo do 110 °C. Po mešanju 60 h raztopino ohladimo in koncentriramo v vakuumu. Ostanek raztopimo v 7 ml metanola in nastalo raztopino segrevamo 30 min. pri refluksu. Zmes ohladimo in obdelamo z nekaj kapljicami koncentriranega vodnega amoniaka in raztopino koncentriramo. Ostanek delno prečistimo s flash kromatografijo na 67 g kremenice, pri čemer eluiramo z 1,5 1 100 : 1 metilen klorid metanol in bogate deleže prečistimo s flash kromatografijo na 32 g kremenice, pri čemer eluiramo s 50 : 50 heksanketil acetatom in nato 50 : 50 : 5 heksanketil acetat:metanol, da dobimo 0,051 g (20 %) olja, kije po XH NMR čist cis morfolin.A solution of 0.33 g (0.77 mmol) of 4-benzyl-2- (S) - (3,5-dichlorobenzyloxy) -3- (S) -phenylmorpholine (from Example 44, step B) and 0.22 g ( 1.54 mmol) of 1-chloroethyl chloroformate in 4.5 ml of 1,2-dichloroethane are placed in a pressure vessel which is immersed in an oil bath heated to 110 ° C. After stirring for 60 h, the solution was cooled and concentrated in vacuo. Dissolve the residue in 7 ml of methanol and heat the resulting solution for 30 min. at reflux. The mixture was cooled and treated with a few drops of concentrated aqueous ammonia and the solution concentrated. The residue was partially purified by flash chromatography on 67 g of quartz, eluting with 1.5 1 100: 1 methylene chloride methanol and the rich portions purified by flash chromatography on 32 g of quartz, eluting with 50: 50 hexanethyl acetate and then 50: 50: 5 hexanacetyl acetate: methanol to give 0.051 g (20%) of an oil which, by X H NMR, is pure cis morpholine.

Masni spekter (FAB): m/Z 468, 466, 464 (maks. 8 %), 338, 340 (M+H, 25 %), 178 (20 %), 162 (100 %), 132 (20 %).Mass spectrum (FAB): m / Z 468, 466, 464 (max. 8%), 338, 340 (M + H, 25%), 178 (20%), 162 (100%), 132 (20%) .

Ή NMR (CDC13, 400 MHz, ppm): δ 1,89 (širok s, 1 H), 3,08 (dd, J = 12,5, 2,9,1 H), 3,23 (td, J = 12,2, 3,6, 1 H), 3,59 (dd, J = 11,3, 2,5, 1 H), 4,03 (td, J = 11,7, 3, 1 H), 4,09 (d, J = 2,4,1 H), 4,37 (d, J = 13,5,1 H), 4,62 (d, J = 13,3,1 H), 4,67 (d, J = 2,5, 1 H), 6,72 (d, J = 1,8, 2 H), 7,14 (t, J = 1,8,1 H), 7,25 - 7,40 (m, 5 H).Ή NMR (CDCl 3 , 400 MHz, ppm): δ 1.89 (broad s, 1H), 3.08 (dd, J = 12.5, 2.9.1 H), 3.23 (td. J = 12.2, 3.6, 1 H), 3.59 (dd, J = 11.3, 2.5, 1 H), 4.03 (td, J = 11.7, 3, 1 H) ), 4.09 (d, J = 2.4.1 H), 4.37 (d, J = 13.5.1 H), 4.62 (d, J = 13.3.1 H), 4.67 (d, J = 2.5, 1 H), 6.72 (d, J = 1.8, 2 H), 7.14 (t, J = 1.8.1 H), 7. 25 - 7.40 (m, 5H).

PRIMER 45EXAMPLE 45

2-(S)-(3,5-diklorobenziloksi)-4-(3-(5-okso-L2,4-triazolo)metil)-3-(S)-fenilmorfolin2- (S) - (3,5-dichlorobenzyloxy) -4- (3- (5-oxo-L2,4-triazolo) methyl) -3- (S) -phenylmorpholine

Korak A: N-metilkarboksi-2-kloroacetamidrazonStep A: N-methylcarboxy-2-chloroacetamidrazone

Raztopino 5,0 g (66,2 mmol) kloroacetonitrila v 35 ml suhega metanola ohladimo do 0 °C in obdelamo z 0,105 g (1,9 mmol) natrijevega metoksida. Ledeno kopel odstranimo in zmes pustimo mešati pri sobni temperaturi 30 minut. K reakcijski zmesi nato dodamo 0,110 ml (1,9 mmol) ocetne kisline in nato 5,8 g (64,9 mmol) metil hidrazinkarboksilata. Po mešanju 30 minut pri sobni temperaturi, suspenzijo koncentriramo v vakuumu, in damo na visok vakuum preko noči, da dobimo 10,5 g (98 %) rumenega prahu, katerega del uporabimo v koraku C spodaj.A solution of 5.0 g (66.2 mmol) of chloroacetonitrile in 35 ml of dry methanol was cooled to 0 ° C and treated with 0.105 g (1.9 mmol) of sodium methoxide. The ice bath was removed and the mixture was allowed to stir at room temperature for 30 minutes. 0.110 ml (1.9 mmol) of acetic acid and then 5.8 g (64.9 mmol) of methyl hydrazincarboxylate are then added to the reaction mixture. After stirring for 30 minutes at room temperature, the suspension was concentrated in vacuo and placed under high vacuum overnight to give 10.5 g (98%) of a yellow powder, a portion of which was used in step C below.

Korak B: 4-(2-(N-metilkarboksi-acetamidrazono)-2-(S)-(3,5-diklorobenziloksi)3-(S)-fenilmorfolinStep B: 4- (2- (N-methylcarboxy-acetamidrazono) -2- (S) - (3,5-dichlorobenzyloxy) 3- (S) -phenylmorpholine

Raztopino 0,050 g (0,15 mmol) 2-(S)-(3,5-diklorobenziloksi)-3-(S)-fenilmorfolina (iz primera 44, korak C), 0,034 g (0,21 mmol) N-metilkarboksi-2-kloroacetamidrazona (iz koraka A) in 0,044 ml (0,25 mmol) Ν,Ν-diizopropiletilamina v 1 ml acetonitrila mešamo 3 ure pri sobni temperaturi. Zmes porazdelimo med 20 ml metilen klorida in 10 ml vode. Plasti ločimo, organsko plast posušimo preko natrijevega sulfata in nato koncentriramo v vakuumu. Ostanek prečistimo s flash kromatografijo na 35 g kremenice, pri čemer eluiramo z 11 50 : 1 : metilen klorid/metanol, nato 500 ml 25 : 1 : 0,05 metilen klorid:metanol:vodni amoniak, da dobimo 70 mg (~ 100 %) produkta kot belo trdno snov.A solution of 0.050 g (0.15 mmol) of 2- (S) - (3,5-dichlorobenzyloxy) -3- (S) -phenylmorpholine (from Example 44, step C), 0.034 g (0.21 mmol) of N-methylcarboxy -2-chloroacetamidrazone (from step A) and 0.044 ml (0.25 mmol) of Ν, di-diisopropylethylamine in 1 ml of acetonitrile were stirred for 3 hours at room temperature. The mixture is partitioned between 20 ml of methylene chloride and 10 ml of water. The layers were separated, the organic layer was dried over sodium sulfate and then concentrated in vacuo. The residue was purified by flash chromatography on 35 g of silica eluting with 11 50: 1: methylene chloride / methanol followed by 500 ml 25: 1: 0.05 methylene chloride: methanol: aqueous ammonia to give 70 mg (~ 100% ) of the product as a white solid.

Masni spekter (FAB): m/Z 469 (M+H, 60 %), 467 (M+H, 100 %), 291 (40 %), 160 (20 %), 158 (25 %).Mass spectrum (FAB): m / Z 469 (M + H, 60%), 467 (M + H, 100%), 291 (40%), 160 (20%), 158 (25%).

Ή NMR (CDC13, 400 MHz, ppm): δ 2,48 (td, J = 3,5, 12,2, 1 H), 2,53 (d, J = 14,6, 1 H), 2,90 (d, J = 11,8,1 H), 3,37 (d, J = 14,6,1 H), 3,52 (d, J = 2,8, 1 H), 3,62 (dm, J = 11,4, 1 H), 3,75 (s, 3 H), 4,14 (td, J = 2,2, 11,8, 1 H), 4,28 (d, J = 13,5, 1 H), 4,58 (d, J = 13,6), 4,60 (d, J = 2,8,1 H), 5,45 (širok s, 2 H), 6,74 (d, J = 1,9,2 H), 7,15 (t, J = 1,9, IH), 7,30-7,46 (m, 6 H).Ή NMR (CDCl 3 , 400 MHz, ppm): δ 2.48 (td, J = 3.5, 12.2, 1 H), 2.53 (d, J = 14.6, 1 H), 2 , 90 (d, J = 11.8.1 H), 3.37 (d, J = 14.6.1 H), 3.52 (d, J = 2.8, 1 H), 3.62 (dm, J = 11.4, 1 H), 3.75 (s, 3 H), 4.14 (td, J = 2.2, 11.8, 1 H), 4.28 (d, J = 13.5, 1H), 4.58 (d, J = 13.6), 4.60 (d, J = 2.8.1 H), 5.45 (broad s, 2 H), 6 , 74 (d, J = 1.9.2 H), 7.15 (t, J = 1.9, 1H), 7.30-7.46 (m, 6 H).

Korak C: 2-(S)-(3,5-diklorobenziloksi)-4-(3-(5-okso-l,2,4-triazolo)metil)3-(S)-fenilmorfolinStep C: 2- (S) - (3,5-Dichlorobenzyloxy) -4- (3- (5-oxo-1,2,4-triazolo) methyl) 3- (S) -phenylmorpholine

Raztopino 0,069 g (0,15 mmol) 4-(2-(N-metilkarboksi-acetamidrazono)-2-(S)-(3,5diklorobenziloksi)-3-(S)-fenilmorfolina (iz koraka B) v 6 ml ksilenov segrevamo 2 uri pri refluksu. Raztopino ohladimo in koncentriramo v vakuumu. Ostanek prečistimo s flash kromatografijo na 35 g silikagela, pri čemer eluiramo s 500 ml 50 : 1 : 0,1 metilen klorid/metanol/vodni amoniak, nato 500 ml 20 : 1 : 0,1 metilen klorid/metanol/vodni amoniak, da dobimo 56 mg (88 %) produkta kot bel prah.A solution of 0.069 g (0.15 mmol) of 4- (2- (N-methylcarboxy-acetamidrazono) -2- (S) - (3,5-dichlorobenzyloxy) -3- (S) -phenylmorpholine (from step B) in 6 ml of xylene The solution was cooled and concentrated in vacuo. The residue was purified by flash chromatography on 35 g of silica gel, eluting with 500 ml of 50: 1: 0.1 methylene chloride / methanol / aqueous ammonia, then 500 ml of 20: 1. : 0.1 methylene chloride / methanol / aqueous ammonia to give 56 mg (88%) of product as a white powder.

Masni spekter (FAB): m/Z 437 (M+H, 65 %), 435 (M+H, 100 %), 259 (85 %), 161 (55 %).Mass spectrum (FAB): m / Z 437 (M + H, 65%), 435 (M + H, 100%), 259 (85%), 161 (55%).

Ή NMR (CDC13, 400 MHz, ppm): δ 2,53 (t, J = 11,7, 3,6, 1 H), 2,88 (d, J = 11,6, 1 H), 2,96 (d, J = 14,3,1 H), 3,54 (d, J = 2,6,1 H), 3,63 (dd, J = 11,6,1,9,1 H), 3,68 (d, J = 14,6, 1 H), 4,16 (t, J = 11,7, 2,2, 1 H), 4,30 (d, J = 13,6), 4,58 (d, J = 2,7, 1 H), 4,67 (d, J = 13,6, 1 H), 6,65 (d, J = 1,8, 2 H), 7,07 (t, J = 1,9, 1 H), 7,29 - 7,44 (m, 5 H), 10,25 (širok s, 1 H), 10,75 (širok s, 1 H).Ή NMR (CDCl 3 , 400 MHz, ppm): δ 2.53 (t, J = 11.7, 3.6, 1 H), 2.88 (d, J = 11.6, 1 H), 2 , 96 (d, J = 14.3.1 H), 3.54 (d, J = 2.6.1 H), 3.63 (dd, J = 11.6.1.9.1 H) , 3.68 (d, J = 14.6, 1H), 4.16 (t, J = 11.7, 2.2, 1H), 4.30 (d, J = 13.6), 4.58 (d, J = 2.7, 1 H), 4.67 (d, J = 13.6, 1 H), 6.65 (d, J = 1.8, 2 H), 7. 07 (t, J = 1.9, 1 H), 7.29 - 7.44 (m, 5 H), 10.25 (broad s, 1 H), 10.75 (broad s, 1 H).

PRIMER 46EXAMPLE 46

2-(S)-(3,5-bis(trifluorometil)benziloksi-4-(metoksikarbonilmetil)-3-(S)-fenilmorfolin2- (S) - (3,5-bis (trifluoromethyl) benzyloxy-4- (methoxycarbonylmethyl) -3- (S) -phenylmorpholine

Raztopino 300 mg (0,74 mmol) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)fenilmorfolina (iz primera 15, korak C) in 0,35 ml (2,0 mmol) DIEA v 5 ml acetonitrila obdelamo z 0,19 ml (2,0 mmol) metil bromoacetata in zmes mešamo 16 ur pri sobni temperaturi. Raztopino nato koncentriramo v vakuumu in ostanek porazdelimo med 30 ml etra in 15 ml 0,5 N vodnega KHSO4. Plasti ločimo in organsko fazo speremo z 10 ml slanice in posušimo preko magenzijevega sulfata. Sledi filtracija, organsko fazo koncentriramo v vakuumu in ostanek prečistimo s flash kromatografijo na 20 g kremenice, pri čemer eluiramo z 80 : 20 heksanketer, da dobimo 351 mg (99 %) produkta.A solution of 300 mg (0.74 mmol) of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) phenylmorpholine (from Example 15, step C) and 0.35 ml (2.0 DIEA in 5 ml of acetonitrile was treated with 0.19 ml (2.0 mmol) of methyl bromoacetate and the mixture was stirred at room temperature for 16 hours. The solution was then concentrated in vacuo and the residue partitioned between 30 ml of ether and 15 ml of 0.5 N aqueous KHSO 4 . The layers were separated and the organic phase was washed with 10 ml of brine and dried over magnesium sulfate. Filtration followed, the organic phase was concentrated in vacuo and the residue was purified by flash chromatography on 20 g of silica, eluting with 80: 20 hexaneter to give 351 mg (99%) of product.

[a]D + 147,3° (c = 1,6, CHC13).[α] D + 147.3 ° (c = 1.6, CHCl 3 ).

Masni spekter (FAB); m/Z 478 (M+H, 40 %), 477 (65 %), 418 (50 %), 250 (95 %), 234 (90 %), 227 (100 %).Mass Spectrum (FAB); m / Z 478 (M + H, 40%), 477 (65%), 418 (50%), 250 (95%), 234 (90%), 227 (100%).

Td NMR (CDC13, 400 MHz, ppm): δ 3,02 (širok d, 2 H), 3,13 (d, J = 16,9,1 H), 3,36 (d, J = 16,8), 3,62 (s, 3 H), 3,69 (dt, J = 11,7, 2,2,1 H), 4,03 (širok s, 1 H), 4,23 - 4,32 (m, 1 H), 4,44 (d, J = 13,3,1 H), 4,68, (d, J = 2,6,1 H), 4,81 (d, J = 13,5,1 H), 7,30 7,38 (m, 3 H), 7,4 - 7,5 (m, 3 H), 7,70 (s, 1 H).Td NMR (CDCl 3 , 400 MHz, ppm): δ 3.02 (broad d, 2 H), 3.13 (d, J = 16.9.1 H), 3.36 (d, J = 16. 8), 3.62 (s, 3 H), 3.69 (dt, J = 11.7, 2.2.1 H), 4.03 (broad s, 1 H), 4.23-4. 32 (m, 1H), 4.44 (d, J = 13.3.1 H), 4.68, (d, J = 2.6.1 H), 4.81 (d, J = 13) , 5.1 H), 7.30 7.38 (m, 3 H), 7.4 - 7.5 (m, 3 H), 7.70 (s, 1 H).

Analiza za C^H^^NO*:Analysis for C ^ H ^^ NO *:

izrač. C 55,35 H 4,43 N 2,93 F 23,88 ugot. C 55,09 H 4,43 N 2,83 F 24,05calcd. C 55.35 H 4.43 N 2.93 F 23.88 found. C 55.09 H 4.43 N 2.83 F 24.05

PRIMER 47EXAMPLE 47

2-(S)-(3.5-bis(trifluorometil)benziloksi_4-(karboksimetil)-3-(S)-fenilmorfolin2- (S) - (3,5-bis (trifluoromethyl) benzyloxy-4- (carboxymethyl) -3- (S) -phenylmorpholine

Raztopino 0,016 g (0,034 mmol) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4(metoksikarbonilmetil)-3-(S)-fenilmorfolina (iz primera 46) v 2 ml THF in 0,5 ml vode obdelamo z 0,027 ml (0,067 mmol) 2,5 N vodnega natrijevega hidroksida in zmes mešamo 5 h pri sobni temperaturi. Zmes obdelamo z 2 kapljicama 2 N vodne HC1 in 3 ml vode in raztopino ekstrahiramo s 15 ml 1 : 1 heksani:etil acetatom. Organsko fazo posušimo preko magnezijevega sulfata, filtriramo in koncentriramo v vakuumu. Ostanek prečistimo s flash kromatografijo na 13 g kremenice, pri čemer eluiramo z 250 ml 100 : 3 : 0,1 metilen klorid:metanol:ocetna kislina, nato 100 ml 50: 2: 0,1 metilen klorid:metanol:ocetna kislina, da dobimo 0,014 g (90 %) olja.A solution of 0.016 g (0.034 mmol) of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4 (methoxycarbonylmethyl) -3- (S) -phenylmorpholine (Example 46) in 2 ml of THF and 0.5 ml of water was treated with 0.027 ml (0.067 mmol) of 2.5 N aqueous sodium hydroxide and the mixture was stirred for 5 h at room temperature. The mixture was treated with 2 drops of 2 N aqueous HCl and 3 ml of water and the solution extracted with 15 ml of 1: 1 hexanes: ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on 13 g of silica eluting with 250 ml of 100: 3: 0,1 methylene chloride: methanol: acetic acid, then 100 ml of 50: 2: 0,1 methylene chloride: methanol: acetic acid, yes 0.014 g (90%) of the oil are obtained.

Masni spekter (FAB): m/Z 464 (M+H, 90 %), 420 (M-CO2, 10 %), 227 (ArCH2, 35 %), 220 (M-OCH2Ar, 100 %), 161 (20 %).Mass spectrum (FAB): m / Z 464 (M + H, 90%), 420 (M-CO 2 , 10%), 227 (ArCH 2 , 35%), 220 (M-OCH 2 Ar, 100%) , 161 (20%).

Ή NMR (CDCI3, 400 MHz, ppm): δ 2,9 (jasen d, 2 H), 3,03 (d, 1 H), 3,33 (d, 1 H), 3,72 (d, 1 H), 3,90 (d, 1 H), 4,25 (t, 1 H), 4,44 (d, 1 H), 4,71 (d, 1 H), 4,79 (d, 1 H), 7,3 - 7,4 (m, 5 H), 7,44 (s, 2 H), 7,71 (s, 1 H).Ή NMR (CDCI 3 , 400 MHz, ppm): δ 2.9 (clear d, 2 H), 3.03 (d, 1 H), 3.33 (d, 1 H), 3.72 (d. 1H), 3.90 (d, 1H), 4.25 (t, 1H), 4.44 (d, 1H), 4.71 (d, 1H), 4.79 (d, 1H). 1 H), 7.3 - 7.4 (m, 5 H), 7.44 (s, 2 H), 7.71 (s, 1 H).

PRIMER 48EXAMPLE 48

2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-((2-aminoetil)aminokarbonilmetil)-3-(S)fenilmorfolin hidroklorid2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4 - ((2-aminoethyl) aminocarbonylmethyl) -3- (S) phenylmorpholine hydrochloride

Raztopino 54 mg (0,11 mmol) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4(karboksimetil)-3-(S)-fenilmorfolina (iz primera 46) in 0,15 ml etilendiamina (2,3 mmol) v 1 ml metanola mešamo 48 ur pri 55 °C. Zmes koncentriramo in ostanek prečistimo s flash kromatografijo na 16 g kremenice, pri čemer eluiramo s 500 ml 50 : 4 : 0,1 metilen klorid:metanol:vodni amoniak, da zagotovimo 57 mg (100 %) olja.A solution of 54 mg (0.11 mmol) of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4 (carboxymethyl) -3- (S) -phenylmorpholine (from Example 46) and 0.15 ml of ethylenediamine (2.3 mmol) in 1 ml of methanol was stirred for 48 hours at 55 ° C. The mixture was concentrated and the residue purified by flash chromatography on 16 g of silica eluting with 500 ml of 50: 4: 0.1 methylene chloride: methanol: aqueous ammonia to provide 57 mg (100%) of the oil.

Olje raztopimo v etru in obdelamo z etrom nasičenim s plinasto HC1. Po koncentraciji v vakuumu dobimo 58 mg (95 %) stabilnega olja.The oil was dissolved in ether and treated with ether saturated with gaseous HC1. Concentration in vacuo gave 58 mg (95%) of a stable oil.

Masni spekter (FAB; prosta baza): m/Z 506 (M+H, 100 %), 418 (15 %), 262 (35 %), 227 (30 %), 173 (40 %).Mass spectrum (FAB; free base): m / Z 506 (M + H, 100%), 418 (15%), 262 (35%), 227 (30%), 173 (40%).

*H NMR (CDC13, 400 MHz, ppm): δ 2,56 (d, J = 15,5,1 H), 2,59 (td, J = 12,0, 3,6,1 H), 2,82 (t, J = 6,5, 2 H), 2,96 (d, J = 11,8, 1 H), 3,21 (d, J = 15,8, 1 H), 3,25 - 3,40 (m, 2 H), 3,65 (d, J = 2,6,1 H), 3,67 (jasen dt, J = 11,4, ~2,1 H), 4,18 (td, J = 11,8, 2,6,1 H), 4,33, (d, J = 13,5,1 H), 4,69 (d, J = 2,7,1 H), 4,79 (d, J = 13,5,1 H), 7,25 7,40 (m, 5 H), 7,46 (s, 2 H), 7,59 (širok t, 1 H), 7,71 (s, 1 H).1 H NMR (CDCl 3 , 400 MHz, ppm): δ 2.56 (d, J = 15.5.1 H), 2.59 (td, J = 12.0, 3.6.1 H), 2.82 (t, J = 6.5, 2 H), 2.96 (d, J = 11.8, 1 H), 3.21 (d, J = 15.8, 1 H), 3. 25 - 3.40 (m, 2 H), 3.65 (d, J = 2.6.1 H), 3.67 (clear dt, J = 11.4, ~ 2.1 H), 4. 18 (td, J = 11.8, 2.6.1 H), 4.33, (d, J = 13.5.1 H), 4.69 (d, J = 2.7.1 H) , 4.79 (d, J = 13.5.1 H), 7.25 7.40 (m, 5 H), 7.46 (s, 2 H), 7.59 (broad t, 1 H) , 7.71 (s, 1H).

PRIMER 49EXAMPLE 49

2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-((3-aminopropil)amino karbonilmetil)-3(S)-fenilmorfolin hidroklorid2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4 - ((3-aminopropyl) amino carbonylmethyl) -3 (S) -phenylmorpholine hydrochloride

Raztopino 59 mg (0,12 mmol) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4(karboksimetil)-3-(S)-fenilmorfolina (iz primera 46) in 0,21 ml 1,3-propilendiamina (2,5 mmol) v 1 ml metanola mešamo 72 ur pri 55 °C. Zmes koncentriramo in ostanek prečistimo s flash kromatografijo na 16 g kremenice, pri čemer eluiramo s 500 ml 10 : 1 : 0,05 metilen klorid:metanol:vodni amoniak, da zagotovimo 56 mg (88 %) olja. Olje raztopimo v metilen kloridu in obdelamo z metilen kloridom, ki je nasičen s plinasto HC1. Po koncentraciji v vakuumu dobimo belo pasto.A solution of 59 mg (0.12 mmol) of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4 (carboxymethyl) -3- (S) -phenylmorpholine (from Example 46) and 0.21 ml 1 , 3-Propylenediamine (2.5 mmol) in 1 ml of methanol was stirred for 72 hours at 55 ° C. The mixture was concentrated and the residue purified by flash chromatography on 16 g of silica eluting with 500 ml of 10: 1: 0.05 methylene chloride: methanol: aqueous ammonia to provide 56 mg (88%) of the oil. The oil is dissolved in methylene chloride and treated with methylene chloride saturated with gaseous HC1. After concentration in vacuo, a white paste is obtained.

Masni spekter (FAB; prosta baza): m/Z 520 (M+H, 100 %), 418 (10 %), 276 (30 %), 227(20 %), 174 (30 %).Mass spectrum (FAB; free base): m / Z 520 (M + H, 100%), 418 (10%), 276 (30%), 227 (20%), 174 (30%).

*H NMR (CDC13, 400 MHz, ppm): δ 1,64 (pentet, J = 6,6 2 H), 2,53 (d, J = 15,5, 1 H), 2,58 (td, J = 12,0, 3,6 1 H), 2,73 (t, J = 6,5, 2 H), 2,92 (d, J = 11,8,1 H), 3,19 (d, J = 15,8,1 H), 3,25 - 3,40 (m, 2 H), 3,62 (d, J = 2,6,1 H), 3,65 (jasen dt, J = 11,4, ~2,1 H NMR (CDCl 3 , 400 MHz, ppm): δ 1.64 (pentet, J = 6.6 2 H), 2.53 (d, J = 15.5, 1 H), 2.58 (td , J = 12.0, 3.6 1 H), 2.73 (t, J = 6.5, 2 H), 2.92 (d, J = 11.8.1 H), 3.19 ( d, J = 15.8.1 H), 3.25 - 3.40 (m, 2 H), 3.62 (d, J = 2.6.1 H), 3.65 (clear dt, J = 11.4, ~ 2,

H), 4,16 (td, J = 11,8, 2,6,1 H), 4,41 (d, J = 13,5,1 H), 4,68 (d, J = 2,7, 1 H), 4,79 (d, J = 13,5,1 H), 7,25 - 7,40 (m, 5 H), 7,45 (s, 2 H), 7,57 (širok t, 1 H), 7,70 (s, 1 H).H), 4.16 (td, J = 11.8, 2.6.1 H), 4.41 (d, J = 13.5.1 H), 4.68 (d, J = 2.7) , 1 H), 4.79 (d, J = 13.5.1 H), 7.25 - 7.40 (m, 5 H), 7.45 (s, 2 H), 7.57 (broad t, 1H), 7.70 (s, 1H).

PRIMER 50EXAMPLE 50

4-benzil-5-(S),6-(R)-dimetil-3-(S)-fenilmorfolin-on in 4-benzil-5-(R),6-(S)-dimetil-3(S)-fenilmorfolinon4-Benzyl-5- (S), 6- (R) -dimethyl-3- (S) -phenylmorpholin-one and 4-benzyl-5- (R), 6- (S) -dimethyl-3 (S) -phenylmorpholinone

K raztopini 1,7 g (7,0 mmol) N-benzil-(S)-fenilglicina (primer 13) v 15 ml metilen klorida pri 0 °C dodamo 6,9 ml (13,9 mmol) trimetilaluminija (2,0 M v toluenu). Po eni uri pri 0 °C po kapljicah dodamo 0,625 ml (7,0 mmol) (+/-)-trans-2,3-epoksi butana (raztopljenega v 2,0 ml metilen klorida) in nato pustimo mešati 16 ur pri 22 °C. Reakcijsko zmes nato prenesemo v drugo bučko, ki vsebuje 30 ml 1 : 1 heksammetilen klorida in 30 ml IM kalijevega natrijevega tartrata in mešamo 2 uri pri 22 °C. Plasti ločimo in vodno plast ekstrahiramo z metilen kloridom (3 x 100 ml). Združene organske plasti speremo s 25 ml nasičene raztopine natrijevega klorida, posušimo preko brezvodnega natrijevega sulfata, filtriramo in koncentriramo v vakuumu.To a solution of 1.7 g (7.0 mmol) of N-benzyl- (S) -phenylglycine (Example 13) in 15 ml of methylene chloride at 0 ° C was added 6.9 ml (13.9 mmol) of trimethylaluminum (2.0 M in toluene). After one hour at 0 ° C, 0.625 ml (7.0 mmol) (+/-) - trans-2,3-epoxy butane (dissolved in 2.0 ml of methylene chloride) was added dropwise and then allowed to stir for 16 hours at 22 ° C. The reaction mixture was then transferred to another flask containing 30 ml of 1: 1 hexammethylene chloride and 30 ml of IM potassium sodium tartrate and stirred for 2 hours at 22 ° C. The layers were separated and the aqueous layer was extracted with methylene chloride (3 x 100 ml). The combined organic layers were washed with 25 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.

Surovi alkohol raztopimo v 25 ml toluena, obdelamo s 93 mg (0,49 mmol) p-toluensulfonske kisline in segrevamo 20 ur na 50 °C. Reakcijsko zmes nato ohladimo in koncentriramo v vakuumu. Ostanek porazdelimo med 15 ml dietil etra in 10 ml nasičenega natrijevega bikarbonata. Plasti ločimo in organsko plast speremo z vodo (3 x 10 ml). Združene organske plasti speremo s 25 ml nasičene raztopine natrijevega klorida, posušimo preko brezvodnega magnezijevega sulfata, filtriramo in koncentriramo v vakuumu. Flash kromatografija na 145 g silikagela, pri čemer uporabimo 1 : 4 v/v etil acetat/heksan kot eluent, da 567 mg laktona z visokim Rf (izomer A) in 388 mg laktona z nizkim Rf (izomer B).The crude alcohol was dissolved in 25 ml of toluene, treated with 93 mg (0.49 mmol) of p-toluenesulfonic acid and heated for 20 hours at 50 ° C. The reaction mixture was then cooled and concentrated in vacuo. The residue was partitioned between 15 ml of diethyl ether and 10 ml of saturated sodium bicarbonate. The layers were separated and the organic layer was washed with water (3 x 10 ml). The combined organic layers were washed with 25 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography on 145 g of silica gel using 1: 4 v / v ethyl acetate / hexane as eluent to give 567 mg of lactone with high R f (isomer A) and 388 mg of lactone with low R f (isomer B).

Ή-NMR (400 MHz, CDC13) δ izomer A: 1,04 (d, 3 H, J = 8,0 Hz), 1,24 (d, 3 H, J = 8,0 Hz), 2,92 (širok qd, 1 H), 3,41 (d, 1 H, J = 16,0 Hz), 3,62 (d, 1 H, J = 16,0 Hz), 4,38 (s, 1 H), 4,96 (širok qd, 1 H), 7,20 - 7,42 (m, 8 H), 7,58 - 7,64 (m, 2 H); izomer B: 1,04 (d, 3 H, J = 10,0 Hz), 1,39 (d, 3 H, J = 10,0 Hz), 3,06 (širok qd, 1 H), 3,53 (d, 1 H, J = 16,0 Hz), 3,81 (d, 1 H, J = 16,0 Hz), 4,33 (s, 1 H), 4,67 (širok qd, 1 H), 7,18 7,50 (m, 10 H).Ή-NMR (400 MHz, CDCl 3 ) δ isomer A: 1.04 (d, 3 H, J = 8.0 Hz), 1.24 (d, 3 H, J = 8.0 Hz), 2. 92 (broad qd, 1 H), 3.41 (d, 1 H, J = 16.0 Hz), 3.62 (d, 1 H, J = 16.0 Hz), 4.38 (s, 1 H), 4.96 (broad qd, 1 H), 7.20 - 7.42 (m, 8 H), 7.58 - 7.64 (m, 2 H); isomer B: 1.04 (d, 3 H, J = 10.0 Hz), 1.39 (d, 3 H, J = 10.0 Hz), 3.06 (broad qd, 1 H), 3. 53 (d, 1 H, J = 16.0 Hz), 3.81 (d, 1 H, J = 16.0 Hz), 4.33 (s, 1 H), 4.67 (broad qd, 1 H), 7.18 7.50 (m, 10 H).

Masni spekter (FAB): m/Z izomer A: 296 (M+H, 100 %), 294 (50 %); izomer B: 296 (M+H, 100 %), 294 (50 %).Mass spectrum (FAB): m / Z isomer A: 296 (M + H, 100%), 294 (50%); isomer B: 296 (M + H, 100%), 294 (50%).

PRIMER 51EXAMPLE 51

2-(R)-(3,5-bis(trifluorometil)benziloksi)-[5-(S),6-(R) ali 5-(R),6-(S)-dimetil]-3-(S)fenilmorfolinon2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) - [5- (S), 6- (R) or 5- (R), 6- (S) -dimethyl] -3- (S ) phenylmorpholinone

Korak A: 4-benzil-2-(R)-(3,5-bis(trifluorometil)-benziloksi)-[5-(S),6-(R) aliStep A: 4-Benzyl-2- (R) - (3,5-bis (trifluoromethyl) -benzyloxy) - [5- (S), 6- (R) or

5-(R\6-(S)-dimetil1-3-(S)-fenilmorfolinon5- (R \ 6- (S) -dimethyl-3- (S) -phenylmorpholinone

Po postopku v primeru 15, korak B, 251 mg (0,85 mmol) izomera A iz primera 50 (4-benzil-[5-(S),6-(R) ali 5-(R)-6-(S)-dimetil]-3-(S)-fenilmorfolinona zagotovi 238 mg (53 %) produkta kot olje.Following the procedure in Example 15, Step B, 251 mg (0.85 mmol) of isomer A of Example 50 (4-benzyl- [5- (S), 6- (R) or 5- (R) -6- (S ) -dimethyl] -3- (S) -phenylmorpholinone provides 238 mg (53%) of the product as an oil.

Ή-NMR (400 MHz, CDCy δ 1,03 (d, 3 H, J = 6,7 Hz), 1,13 (d, 3 H, J = 6,6 Hz), 2,61 (qd, 1 H, J = 2,2 & 6,6 Hz), 3,26 (d, 1 H, J = 13,9 Hz), 3,55 (d, 1 H, J = 13,9 Hz), 3,63 (d, 1 H, J = 7,6 Hz), 4,01 (qd, 1 H, J = 2,3 & 6,6 Hz), 4,44 (d, 1 H, J = 13,1 Hz), 4,53 (d, 1 H, J = 7,7 Hz), 4,71 (s, 1 H), 4,85 (d, 1 H, J = 13,2 Hz), 7,20 - 7,35 (m, 9 H), 7,46 - 7,48 (m, 2 H), 7,67 (s, 1 H), 7,81 (s, 1 H).Ή-NMR (400 MHz, CDCl3 δ 1.03 (d, 3 H, J = 6.7 Hz), 1.13 (d, 3 H, J = 6.6 Hz), 2.61 (qd, 1 H, J = 2.2 & 6.6 Hz), 3.26 (d, 1 H, J = 13.9 Hz), 3.55 (d, 1 H, J = 13.9 Hz), 3, 63 (d, 1 H, J = 7.6 Hz), 4.01 (qd, 1 H, J = 2.3 & 6.6 Hz), 4.44 (d, 1 H, J = 13.1 Hz), 4.53 (d, 1 H, J = 7.7 Hz), 4.71 (s, 1 H), 4.85 (d, 1 H, J = 13.2 Hz), 7.20 - 7.35 (m, 9 H), 7.46 - 7.48 (m, 2 H), 7.67 (s, 1 H), 7.81 (s, 1 H).

Masni spekter (FAB); m/Z 523 (M+H, 100 %), 296 (95 %), 280 (40 %), 227 (50 %).Mass Spectrum (FAB); m / Z 523 (M + H, 100%), 296 (95%), 280 (40%), 227 (50%).

Korak B: 2-(R)-(3,5-bis-(trifluorometil)benziloksi)-[5-(S),6-(R) aliStep B: 2- (R) - (3,5-bis- (trifluoromethyl) benzyloxy) - [5- (S), 6- (R) or

5-(R),6-(S)-dimetill-3-(S)-fenilmorfolinon5- (R), 6- (S) -dimethyl-3- (S) -phenylmorpholinone

Po postopku v primeru 15, korak C, 260 mg izhodnega materiala iz koraka A [pridobljenega iz izomera A v primeru 50 (4-benzil-2-(R)-(3,5bis(trifluorometil)benziloksi)-[5-(S),6-(R) ali 5-(R),6-(S)-dimetil]-3-(S)fenilmorfolinona)] zagotovi 122 mg (57 %) produkta kot olje.Following the procedure in Example 15, Step C, 260 mg of starting material from Step A [obtained from isomer A in Example 50 (4-benzyl-2- (R) - (3,5bis (trifluoromethyl) benzyloxy) - [5- (S , 6- (R) or 5- (R), 6- (S) -dimethyl] -3- (S) phenylmorpholinone)] provided 122 mg (57%) of the product as an oil.

Ή-NMR (400 MHz, CDC13) δ 1,19 (d, 3H, J = 6,5 Hz), 1,27 (d, 3 H, J = 6,7 Hz), 2,97 (qd, 1 H, J = 2,9 & 6,9 Hz), 3,96 (d, 1 H, J = 7,7 Hz), 4,08 - 4,11 (m, 2 H), 4,39 (d, 1 H, J = 7,7 Hz), 4,50 (d, 1 H, J = 13,3 Hz), 4,88 (d, 1 H, J = 13,2 Hz), 7,27 - 7,33 (m, 3 H), 7,40 - 7,42 (m, 4 H), 7,67 (s, 1 H).Ή-NMR (400 MHz, CDCl 3 ) δ 1.19 (d, 3H, J = 6.5 Hz), 1.27 (d, 3 H, J = 6.7 Hz), 2.97 (qd. 1 H, J = 2.9 & 6.9 Hz), 3.96 (d, 1 H, J = 7.7 Hz), 4.08 - 4.11 (m, 2 H), 4.39 ( d, 1 H, J = 7.7 Hz), 4.50 (d, 1 H, J = 13.3 Hz), 4.88 (d, 1 H, J = 13.2 Hz), 7.27 - 7.33 (m, 3 H), 7.40 - 7.42 (m, 4 H), 7.67 (s, 1 H).

Masni spekter (FAB): m/Z 434 (M+H, 45 %), 227 (35 %), 206 (40 %), 190 (100 %).Mass spectrum (FAB): m / Z 434 (M + H, 45%), 227 (35%), 206 (40%), 190 (100%).

PRIMER 52EXAMPLE 52

2-(S)-(3,5-bis-(trifluorometil)benziloksi)-[5-(R),6-(Sl ali2- (S) - (3,5-bis- (trifluoromethyl) benzyloxy) - [5- (R), 6- (Sl or

5-(S),6-(R)-dimetill-3-(S)-fenilmorfolinon5- (S), 6- (R) -dimethyl-3- (S) -phenylmorpholinone

Korak A: 4-benzil-2-(S)-(3,5-bis(trifluorometil)-benziloksi)-[5-(R),6-(S) aliStep A: 4-Benzyl-2- (S) - (3,5-bis (trifluoromethyl) -benzyloxy) - [5- (R), 6- (S) or

5-(S\6-(R)-dimetill-3-(S)-fenilmorfolinon5- (S \ 6- (R) -dimethyl-3- (S) -phenylmorpholinone

Po postopku v primeru 15 korak B, 449 mg (1,52 mmol) izomera B iz primera 50 (4benzil-[5-(R),6-(S) ali 5-(S)-6-(R)-dimetil]-3-(S)-fenilmorfolinona zagotovi 400 mg (51 %) produkta kot olje.Following the procedure in Example 15, step B, 449 mg (1.52 mmol) of isomer B of Example 50 (4benzyl- [5- (R), 6- (S) or 5- (S) -6- (R) -dimethyl ] -3- (S) -phenylmorpholinone provides 400 mg (51%) of the product as an oil.

Ή-NMR (400 MHz, CDC13) δ 0,90 (d, 3 H, J = 6,8 Hz), 1,37 (d, 3 H, J = 6,6 Hz), 2,86 - 2,89 (širok qd, 1 H), 3,47 (d, 1 H, J = 15,0 Hz), 3,82 - 3,85 (m, 2 H), 3,99 - 4,02 (širok qd, 1 H), 4,45 (d, 1 H, J = 13,6 Hz), 4,81 (d, 1 H, J = 2,0 Hz), 4,87 (d, 1 H, J = 13,5 Hz), 7,17 - 7,83 (m, 13 H).Ή-NMR (400 MHz, CDCl 3 ) δ 0.90 (d, 3 H, J = 6.8 Hz), 1.37 (d, 3 H, J = 6.6 Hz), 2.86 - 2 , 89 (broad qd, 1 H), 3.47 (d, 1 H, J = 15.0 Hz), 3.82 - 3.85 (m, 2 H), 3.99 - 4.02 (broad qd, 1 H), 4.45 (d, 1 H, J = 13.6 Hz), 4.81 (d, 1 H, J = 2.0 Hz), 4.87 (d, 1 H, J = 13.5 Hz), 7.17 - 7.83 (m, 13 H).

Korak B: 2-(S)-(3,5-bis(trifluorometil)benziloksi)-[5-(S),6-(R) aliStep B: 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) - [5- (S), 6- (R) or

5-(R).6-(S)-dimetill-3-(S)-fenilmorfolinon5- (R) .6- (S) -dimethyl-3- (S) -phenylmorpholinone

Po postopku v primeru 15, korak C, 400 mg izhodnega materiala iz koraka A [pridobljenega iz izomera B v primeru 50 (4-benzil-2-(S)-(3,5-bis(trifluorometil)benziloksi-[5-(R),6-(S) ali 5-(S),6-(R)-dimetil]-3-(S)-fenilmorfolinona)] zagotovi 230 mg (69 %) produkta kot olje.Following the procedure in Example 15, Step C, 400 mg of starting material from Step A [obtained from isomer B in Example 50 (4-benzyl-2- (S) - (3,5-bis (trifluoromethyl) benzyloxy- [5- ( R), 6- (S) or 5- (S), 6- (R) -dimethyl] -3- (S) -phenylmorpholinone)] provided 230 mg (69%) of the product as an oil.

Ή-NMR (400 MHz, CDC13) δ 1,08 (d, 3 H, J = 6,7 Hz), 1,38 (d, 3 H, J = 7,0 Hz), 3,41 - 3,45 (širok qd, 1 H), 3,85 - 3,89 (širok qd, 1 H), 4,16 (d, 1 H, J = 2,9 Hz), 4,49 (d, 1 H, J = 13,6 Hz), 4,71 (d, 1 H, J = 2,9 Hz), 4,82 (d, 1 H, J = 13,6 Hz), 7,25 - 7,36 (m, 7 H), 7,66 (s, 1 H).Ή-NMR (400 MHz, CDCl 3 ) δ 1.08 (d, 3 H, J = 6.7 Hz), 1.38 (d, 3 H, J = 7.0 Hz), 3.41 - 3 , 45 (broad qd, 1 H), 3.85 - 3.89 (wide qd, 1 H), 4.16 (d, 1 H, J = 2.9 Hz), 4.49 (d, 1 H) , J = 13.6 Hz), 4.71 (d, 1 H, J = 2.9 Hz), 4.82 (d, 1 H, J = 13.6 Hz), 7.25 - 7.36 (m, 7H), 7.66 (s, 1H).

Masni spekter (FAB); m/Z 434 (M+H, 35 %), 227 (40 %), 206 (40 %), 190 (100 %).Mass Spectrum (FAB); m / Z 434 (M + H, 35%), 227 (40%), 206 (40%), 190 (100%).

PRIMER 53EXAMPLE 53

2-(R)-(3,5-bis(trifluorometil)benziloksi)-4-(3-(l,2,4-triazolo)metil)-[5-(S),6-(R) ali2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (3- (1,2,4-triazolo) methyl) - [5- (S), 6- (R) or

- (R) ,6-(S)-dimetill -3-(S) -fenilmorfolinon- (R), 6- (S) -dimethyl-3- (S) -phenylmorpholinone

2'mes 62 mg (0,14 mmol) 2-(R)-(3,5-bis(trifluorometil)benziloksi)-[5-S),6-(R) ali 5-(R),6-(S)-dimetil]-3-(S)-fenilmorfolinona (iz primera 51, korak B), 62 mg (0,45 mmol) brezvodnega kalijevega karbonata in 26 mg (0,19 mmol) N-formil-2kloroacetamidrazona (iz primera 17, korak A) v 2,0 ml N,N-dimetilformamida segrevamo 2 uri do 60 °C in nato 1,5 ure na 118 °C. Zmes nato pustimo, da se ohladi na sobno temperaturo in jo nato pogasimo s 5 ml vode in razredčimo s 15 ml etil acetata. Plasti ločimo in organsko plast speremo z etil acetatom (2 x 10 ml). ŽSdružene organske plasti speremo z 10 ml slanice, posušimo preko brezvodnega magnezijevega sulfata, filtriramo in koncentriramo v vakuumu. Flash kromatografija na 42 g silikagela, pri čemer uporabimo 95 : 5 metilen klorid/metanol kot eluent, da 42 mg (57 %) bistrega olja.2'mes 62 mg (0.14 mmol) 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) - [5-S), 6- (R) or 5- (R), 6- ( S) -dimethyl] -3- (S) -phenylmorpholinone (from example 51, step B), 62 mg (0.45 mmol) of anhydrous potassium carbonate and 26 mg (0.19 mmol) of N-formyl-2chloroacetamidrazone (from example 17, step A) in 2.0 ml of N, N-dimethylformamide is heated to 60 ° C for 2 hours and then at 118 ° C for 1.5 hours. The mixture was then allowed to cool to room temperature and then quenched with 5 ml of water and diluted with 15 ml of ethyl acetate. The layers were separated and the organic layer was washed with ethyl acetate (2 x 10 ml). The combined organic layers were washed with 10 ml of brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography on 42 g of silica gel using 95: 5 methylene chloride / methanol as eluant to give 42 mg (57%) of a clear oil.

Ή-NMR (400 MHz, CDC13) δ 1,13 (d, 3 H, J = 6,5 Hz), 1,19 (d, 3 H, J = 6,5 Hz), 2,65 (qd, 1 H, J = 1,96 & 6,5 Hz), 3,58 (d, 1 H, J = 15,5 Hz), 3,65 (d, 1 H, J = 7,7 Hz), 3,75 (d, 1 H, J = 15,4 Hz), 4,06 (qd, 1 H, J = 2,2 & 6,6 Hz), 4,45 (d, 1 H, J = 13,2 Hz), 4,54 (d, 1 H), J = 7,7 Hz), 4,84 (d, 1 H, J = 13,2 Hz), 7,28 - 7,37 (m, 7 H), 7,67 (s, 1 H), 7,89 (s, 1 H).Ή-NMR (400 MHz, CDCl 3 ) δ 1.13 (d, 3 H, J = 6.5 Hz), 1.19 (d, 3 H, J = 6.5 Hz), 2.65 (qd , 1 H, J = 1.96 & 6.5 Hz), 3.58 (d, 1 H, J = 15.5 Hz), 3.65 (d, 1 H, J = 7.7 Hz), 3.75 (d, 1 H, J = 15.4 Hz), 4.06 (qd, 1 H, J = 2.2 & 6.6 Hz), 4.45 (d, 1 H, J = 13 , 2 Hz), 4.54 (d, 1 H), J = 7.7 Hz), 4.84 (d, 1 H, J = 13.2 Hz), 7.28 - 7.37 (m, 7 H), 7.67 (s, 1 H), 7.89 (s, 1 H).

Masni spekter (FAB); m/Z 516 (M+H, 52 %), 287 (28 %), 271 (100 %), 227 (40 %), 202 (38 %).Mass Spectrum (FAB); m / Z 516 (M + H, 52%), 287 (28%), 271 (100%), 227 (40%), 202 (38%).

PRIMER 54EXAMPLE 54

2-(R)-(3,5-bis(trifluorometil)benziloksi)-4-(3-(5-okso-l,2,4-triazolo)metil)-[5-(S),6-(R) ali 5-(R).6-(S)-dimetill-3-(S)-fenilmorfolinon2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (3- (5-oxo-1,2,4-triazolo) methyl) - [5- (S), 6- (R ) or 5- (R) 6- (S) -dimethyl-3- (S) -phenylmorpholinone

Raztopino 96 mg (0,22 mmol) 2-(R)-(3,5-bis(trifluorometil)benziloksi)-[5-(S),6-(R) ali 5-(R),6-(S)-dimetil]-3-(S)-fenilmorfolinona (iz primera 51, korak B), 92 mg (0,66 mmol) kalijevega karbonata in 48 mg (0,29 mmol) N-metilkarboksi-2Idoroacetamidrazona (iz primera 18, korak A) v 4 ml DMF segrevamo 1,5 h pri 60 °C in 3,5 h pri 120 °C. Zmes ohladimo na sobno temperaturo in porazdelimo med 15 ml vode in 25 ml etil acetata. Vodno plast ekstrahiramo s 3 x 10 ml etil acetata, združene organske plasti speremo z 10 ml slanice, posušimo preko natrijevega sulfata, filtriramo in koncentriramo v vakuumu. Ostanek delno prečistimo s flash kromatografijo na 42 g silikagela, pri čemer uporabimo 2 1 98 : 2 v/v metilen klorid/metanol kot eluent, in bogate dele prečistimo pod enakimi pogoji, da dobimo 38 mg (33 %) bistrega olja.96 mg (0.22 mmol) solution of 2- (R) - (3,5-bis (trifluoromethyl) benzyloxy) - [5- (S), 6- (R) or 5- (R), 6- (S ) -dimethyl] -3- (S) -phenylmorpholinone (from example 51, step B), 92 mg (0.66 mmol) of potassium carbonate and 48 mg (0.29 mmol) of N-methylcarboxy-2Idoroacetamidrazone (from example 18, step A) in 4 ml of DMF was heated for 1.5 h at 60 ° C and 3.5 h at 120 ° C. The mixture was cooled to room temperature and partitioned between 15 ml of water and 25 ml of ethyl acetate. The aqueous layer was extracted with 3 x 10 ml ethyl acetate, the combined organic layers were washed with 10 ml brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was partially purified by flash chromatography on 42 g of silica gel using 2 1 98: 2 v / v methylene chloride / methanol as eluent, and the rich portions were purified under the same conditions to give 38 mg (33%) of a clear oil.

‘H-NMR (400 MHz, CDC13) δ 1,09 (d, 3 H, J = 6,5 Hz), 1,20 (d, 3 H, J = 6,6 Hz), 2,64 (qd, 1 H, J = 2,4 & 6,6 Hz), 3,33 (s, 1 H), 3,56 (d, 1 H, J = 7,6 Hz), 4,11 (qd, 1 H, J = 2,4 & 6,6 Hz), 4,41 (d, 1 H, J = 13,2 Hz), 4,57 (d, 1 H), J = 7,7 Hz), 4,82 (d, 1 H, J = 13,2 Hz), 7,25 - 7,30 (m, 5 H), 7,40 (d, 2 H), J = 5,7 Hz), 7,65 (s, 1 H), 9,46 (s, 1 H), 10,51 (s, 1 H).1 H-NMR (400 MHz, CDCl 3 ) δ 1.09 (d, 3 H, J = 6.5 Hz), 1.20 (d, 3 H, J = 6.6 Hz), 2.64 ( qd, 1 H, J = 2.4 & 6.6 Hz), 3.33 (s, 1 H), 3.56 (d, 1 H, J = 7.6 Hz), 4.11 (qd, 1 H, J = 2.4 & 6.6 Hz), 4.41 (d, 1 H, J = 13.2 Hz), 4.57 (d, 1 H), J = 7.7 Hz), 4.82 (d, 1 H, J = 13.2 Hz), 7.25 - 7.30 (m, 5 H), 7.40 (d, 2 H), J = 5.7 Hz), 7 , 65 (s, 1H), 9.46 (s, 1H), 10.51 (s, 1H).

Masni spekter (FAB): m/Z 531 (M+H, 98 %), 287 (100 %), 227 (80 %), 189 (65 %).Mass spectrum (FAB): m / Z 531 (M + H, 98%), 287 (100%), 227 (80%), 189 (65%).

PRIMER 55EXAMPLE 55

2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-(3-(l,2,4-triazolo)metil)-i5-(R),6-(S) ali2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (3- (1,2,4-triazolo) methyl) -1,5- (R), 6- (S) or

5-(S),6-(R)-dimetil]-3-(S)-fenilmorfolinon5- (S), 6- (R) -dimethyl] -3- (S) -phenylmorpholinone

Po postopku v primeru 53, 75 mg (0,17 mmol) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-[5-(R),6-(S) ali 5-(S),6-(R)-dimetil]-3-(S)-fenilmorfolinona (iz primera 52, korak B) zagotovi po flash kromatografiji na 73 g silikagela, pri čemer uporabimo 98: 2 v/v metilen klorid/metanol kot eluent, 46 mg (52 %) rumenega olja.Following the procedure in Example 53, 75 mg (0.17 mmol) of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) - [5- (R), 6- (S) or 5- (S) , 6- (R) -dimethyl] -3- (S) -phenylmorpholinone (from Example 52, step B) is provided by flash chromatography on 73 g of silica gel, using 98: 2 v / v methylene chloride / methanol as eluent, 46 mg (52%) of yellow oil.

jH-NMR (400 MHz, CDC13) δ 1,04 (d, 3 H, J = 6,6 Hz), 1,46 (d, 3 H, J = 6,7 Hz), 3,05 - 3,08 (m, 1 H), 3,74 - 3,81 (m, 2 H), 3,91 - 3,95 (m, 2 H), 4,41 (d, 1 H, J = 13,2 Hz), 4,69 (d, 1 H, J = 3,2 Hz), 4,82 (d, 1 H, J = 13,5 Hz), 7,31 - 7,35 (m, 5 H), 7,43 7,45 (m, 2 H), 7,68 (s, 1 H), 7,91 (s, 1 H). j H-NMR (400 MHz, CDCl 3 ) δ 1.04 (d, 3 H, J = 6.6 Hz), 1.46 (d, 3 H, J = 6.7 Hz), 3.05 - 3.08 (m, 1 H), 3.74 - 3.81 (m, 2 H), 3.91 - 3.95 (m, 2 H), 4.41 (d, 1 H, J = 13) , 2 Hz), 4.69 (d, 1 H, J = 3.2 Hz), 4.82 (d, 1 H, J = 13.5 Hz), 7.31 - 7.35 (m, 5 H), 7.43 7.45 (m, 2 H), 7.68 (s, 1 H), 7.91 (s, 1 H).

Masni spekter (ΕΙ): m/Z 432 (36 %), 287 (60 %), 270 (65 %), 227 ( 30 %), 187 (48 %), 83 (100 %).Mass spectrum (SW): m / Z 432 (36%), 287 (60%), 270 (65%), 227 (30%), 187 (48%), 83 (100%).

100100

PRIMER 56EXAMPLE 56

2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-(3-(5-okso-l,2,4-triazoIo)metil)-[5-(R),6(S) ali 5-(S).6-(R)-dimetill-3-(S)-fenilmorfolinon2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (3- (5-oxo-1,2,4-triazolo) methyl) - [5- (R), 6 (S) or 5- (S) 6- (R) -dimethyl-3- (S) -phenylmorpholinone

Po postopku v primeru 54, 86 mg (0,2 mmol) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-[5-(R),6-(S) ali 5-(S),6-(R)-dimetil]-3-(S)-fenilmorfolinona (iz primera 47, korak B) zagotovi, po flash kromatografiji na 73 g silikagela, pri čemer uporabimo 95 : 5 v/v metilen klorid/metanol kot eluent, 32 mg (30 %) rumenega olja.Following the procedure in Example 54, 86 mg (0.2 mmol) of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) - [5- (R), 6- (S) or 5- (S) , 6- (R) -dimethyl] -3- (S) -phenylmorpholinone (from Example 47, step B) provides, by flash chromatography on 73 g of silica gel, using 95: 5 v / v methylene chloride / methanol as eluent , 32 mg (30%) of yellow oil.

Ή-NMR (400 MHz, CDC13) δ 1,03 (d, 3 H, J = 6,7 Hz), 1,40 (d, 3 H, J = 6,8 Hz), 3,00 (qd, 1 H, J = 3,8 & 6,8 Hz), 3,44 (d, 1 H, J = 16,1 Hz), 3,63 (d, 1 H, J = 16,0 Hz), 3,82 (d, 1 H, J = 3,3 Hz), 3,95 (qd, 1 H, J = 3,7 & 6,7 Hz), 4,43 (d, 1 H, J = 13,5 Hz), 4,73 (d, 1 H, J = 3,3 Hz), 4,84 (d, 1 H, J = 13,6 Hz), 7,28 : 7,47 (m, 7 H), 7,68 (s, IH), 9,52 (d, 2 H).Ή-NMR (400 MHz, CDCl 3 ) δ 1.03 (d, 3 H, J = 6.7 Hz), 1.40 (d, 3 H, J = 6.8 Hz), 3.00 (qd , 1 H, J = 3.8 & 6.8 Hz), 3.44 (d, 1 H, J = 16.1 Hz), 3.63 (d, 1 H, J = 16.0 Hz), 3.82 (d, 1 H, J = 3.3 Hz), 3.95 (qd, 1 H, J = 3.7 & 6.7 Hz), 4.43 (d, 1 H, J = 13 , 5 Hz), 4.73 (d, 1 H, J = 3.3 Hz), 4.84 (d, 1 H, J = 13.6 Hz), 7.28: 7.47 (m, 7 H), 7.68 (s, 1H), 9.52 (d, 2H).

Masni spekter (FAB): m/Z 531 (M+H, 100 %), 287 (55 %), 227 (25 %), 147 (50 %).Mass spectrum (FAB): m / Z 531 (M + H, 100%), 287 (55%), 227 (25%), 147 (50%).

PRIMER 57EXAMPLE 57

2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-(2-(l-(4-benzil)piperidino)etil)-3-(S)-fenilmorfolin2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (2- (1- (4-benzyl) piperidino) ethyl) -3- (S) -phenylmorpholine

K raztopini 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-fenilmorfolina (50 mg, 0,12 mmol) in 4-benzil-l-(2-kloroetil)piperidin hidroklorida (50 mg, 0,18 mmol) v acetonitrilu (0,5 ml) dodamo diizopropiletilamin (0,065 ml,0,36 mmol) pri sobni temperaturi. Po 60 urah, tankoplastna tekočinska kromatografija (5 % MeOH/2 % Et3N/93 % EtOAc) kaže, da je reakcija le delno končana. Reakcijsko zmes razredčimo z metilen kloridom in speremo z vodo, nato slanico, posušimo preko natrijevega sulfata in uparimo. Tankoplastna tekočinska kromatografija (5 % MeOHN/ 2 % Et3N/93 % EtOAc) zagotovi 36 mg (50 %) naslovne spojine kot olje.To a solution of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) -phenylmorpholine (50 mg, 0.12 mmol) and 4-benzyl-1- (2-chloroethyl) piperidine hydrochloride (50 mg, 0.18 mmol) in acetonitrile (0.5 ml) was added diisopropylethylamine (0.065 ml, 0.36 mmol) at room temperature. After 60 hours, thin layer liquid chromatography (5% MeOH / 2% Et 3 N / 93% EtOAc) indicated that the reaction was only partially complete. The reaction mixture was diluted with methylene chloride and washed with water, then brine, dried over sodium sulfate and evaporated. Thin-layer liquid chromatography (5% MeOHN / 2% Et 3 N / 93% EtOAc) provided 36 mg (50%) of the title compound as an oil.

Ή-NMR (400 MHz, CDC13) δ 1,1 -1,4 (m, 2 H), 1,4 -1,65 (2 m, 4 H), 1,65 - 2,05 (m, 3 H), 2,05 - 2,3 (m, 1 H), 2,35 - 2,5 (m in d, J = 7 Hz, 3 H), 2,55 (širok t, J = 11 Hz, 1 H), 2,65 - 2,8 (m, 2 H), 3,09 (d, J = 11 Hz, 1 H), 3,50 (d, J = 2,5 Hz, 1 H), 3,66 (dd, J = 2 in 11 Hz, 1 H), 4,15 (dt, J = 2 in 12 Hz, 1 H), 4,38 in 4,75 (AB q, J = 13 Hz, 2 H), 4,61 (d, J = 2,5 Hz, 1 H), 7,06 (d, J = 7 Hz, 2 H), 7,15 (t, J = 7 Hz, 1 H), 7,2 - 7,35 (m, 5 H), 7,36 (m, 4 H), 7,75 (s, 1 H).Ή-NMR (400 MHz, CDCl 3 ) δ 1.1 -1.4 (m, 2 H), 1.4 -1.65 (2 m, 4 H), 1.65-2.05 (m, 3 H), 2.05-2.3 (m, 1 H), 2.35-2.5 (m and d, J = 7 Hz, 3 H), 2.55 (broad t, J = 11 Hz , 1 H), 2.65-2.8 (m, 2 H), 3.09 (d, J = 11 Hz, 1 H), 3.50 (d, J = 2.5 Hz, 1 H) , 3.66 (dd, J = 2 and 11 Hz, 1 H), 4.15 (dt, J = 2 and 12 Hz, 1 H), 4.38 and 4.75 (AB q, J = 13 Hz , 2 H), 4.61 (d, J = 2.5 Hz, 1 H), 7.06 (d, J = 7 Hz, 2 H), 7.15 (t, J = 7 Hz, 1 H) ), 7.2-7.35 (m, 5H), 7.36 (m, 4H), 7.75 (s, 1H).

101101

PRIMER 58 (S)-(4-fluorofenil)glicinEXAMPLE 58 (S) - (4-Fluorophenyl) glycine

Korak A: 3-(4-fluorofenil)acetil-4-(S)-benzil-2-oksazolidinonStep A: 3- (4-Fluorophenyl) acetyl-4- (S) -benzyl-2-oxazolidinone

V peči posušeno, 11 3-vratno bučko, opremljeno s prekatom, vhodom za dušik, termometrom in magnetnim mešalom, izperemo z dušikom in napolnimo z raztopino 5,09 g (33,0 mmol) 4-fluorofenilocetne kisline v 100 ml brezvodnega etra. Raztopino ohladimo do -10 °C in jo obdelamo s 5,60 ml (40,0 mmol) trietilamina, čemur sledijo 4,30 ml(35,0 mmol) trimetilacetil klorida. Takoj se tvori bela oborina. Nastalo zmes mešamo pri -10 °C 40 minut, nato jo ohladimo do -78 °C.The oven-dried, 11-necked flask equipped with a chamber, a nitrogen inlet, a thermometer and a magnetic stirrer was washed with nitrogen and filled with a solution of 5.09 g (33.0 mmol) of 4-fluorophenylacetic acid in 100 ml of anhydrous ether. The solution was cooled to -10 ° C and treated with 5.60 ml (40.0 mmol) of triethylamine followed by 4.30 ml (35.0 mmol) of trimethylacetyl chloride. A white precipitate immediately forms. The resulting mixture was stirred at -10 ° C for 40 minutes, then cooled to -78 ° C.

V peči posušeno, 250 ml bučko z okroglim dnom, opremljeno s prekatom in magnetnim mešalom, speremo z dušikom in napolnimo z raztopino 5,31 g (30,0 mmol) 4-(S)-benzil-2-oksazolidinona v 40 ml suhega THF. Raztopino mešamo v suhi led/aceton kopeli 10 minut, nato počasi dodamo 18,8 ml 1,6 M n-butillitijeve raztopine v heksanih. Po 10 minutah k zmesi v 3-vratni bučki preko cevke dodamo raztopino litiiranega oksazolidinona. Hladilno kopel odstranimo od nastale zmesi in temperaturo pustimo, da se dvigne do 0 °C. Reakcijsko zmes pogasimo s 100 ml nasičene raztopine vodnega amonijevega klorida, prenesemo v 11 bučko, in eter in THF odstranimo v vakuumu. Koncentrirano zmes porazdelimo med 300 ml metilen klorida in 50 ml vode in plasti ločimo. Organsko plast speremo z 200 ml 2 N vodne raztopine klorovodikove kisline, 300 ml nasičene vodne raztopine natrijevega bikarbonata, posušimo preko magnezijevega sulfata in koncentriramo v vakuumu. Flash kromatografija na 400 g silikagela, pri čemer uporabimo 3 : 2 v/v heksani/eter kot eluent, da 8,95 g olja, ki se ob stanju počasi strdi. Prekristalizacija iz 10 : 1 heksani/eter zagotovi 7,89 g (83 %) naslovne spojine kot bele trdne snovi, tal. 64 do 66 °C.The oven-dried, 250 ml round-bottom flask equipped with a chamber and a magnetic stirrer was washed with nitrogen and filled with a solution of 5.31 g (30.0 mmol) of 4- (S) -benzyl-2-oxazolidinone in 40 ml of dry THF. The solution was stirred in a dry ice / acetone bath for 10 minutes, then 18.8 ml of a 1.6 M n-butyllithium solution in hexanes was slowly added. After 10 minutes, a solution of lithiated oxazolidinone was added to the mixture in a 3-neck flask via a tube. The cooling bath was removed from the resulting mixture and the temperature was allowed to rise to 0 ° C. The reaction mixture was quenched with 100 ml of saturated aqueous ammonium chloride solution, transferred to 11 flasks, and the ether and THF removed in vacuo. The concentrated mixture was partitioned between 300 ml of methylene chloride and 50 ml of water and the layers separated. The organic layer was washed with 200 ml of 2 N aqueous hydrochloric acid, 300 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 400 g of silica gel using 3: 2 v / in hexanes / ether as eluant to give 8.95 g of an oil which slowly solidifies under condition. Recrystallization from 10: 1 hexanes / ether provided 7.89 g (83%) of the title compound as a white solid, m.p. 64 to 66 ° C.

Masni spekter (FAB); m/Z 314 (M+H, 100 %), 177 (M-ArCH2CO+H, 85 %).Mass Spectrum (FAB); m / Z 314 (M + H, 100%), 177 (M-ArCH 2 CO + H, 85%).

'H-NMR (400 MHz, CDC13) δ 2,76 (dd, 1 H, J = 13,2, 9,2), 3,26 (dd, J = 13,2, 3,2), 4,16 - 4,34 (m, 4 H), 4,65 - 4,70 (m, 1 H), 7,02 - 7,33 (m, 9 H).1 H-NMR (400 MHz, CDCl 3 ) δ 2.76 (dd, 1 H, J = 13.2, 9.2), 3.26 (dd, J = 13.2, 3.2), 4 , 16 - 4.34 (m, 4 H), 4.65 - 4.70 (m, 1 H), 7.02 - 7.33 (m, 9 H).

Analiza za ClgH16FNO3: izrač. C 69,00 ugot. C 68,86Analysis for C lg H 16 FNO 3 : Calc. C 69.00 found C, 68.86

H 5,15 H 5,14H 5.15 H 5.14

N 4,47 N 4,48N, 4.47; N, 4.48

F 6,06 F 6,08F 6.06 F 6.08

102102

Korak B: 3-((S)-azido-(4-fluorofenil))acetil-4-(S)-benzil-2-oksazolidinonStep B: 3 - ((S) -azido- (4-fluorophenyl) acetyl-4- (S) -benzyl-2-oxazolidinone

V peči posušeno, 11 3-vratno bučko, opremljeno s prekatom, vhodom za dušik, termometrom in magnetnim mešalom, speremo z dušikom in napolnimo z raztopino 58,0 ml 1 M raztopine kalijevega bis(trimetilsilil)amida v toluenu in 85 ml THF, in ohladimo do -78 °C. V peči posušeno, 250 ml bučko z okroglim dnom, opremljeno s prekatom in magnetnim mešalom, speremo z dušikom in napolnimo z raztopino 7,20 g (23,0 mmol) 3-(4-fluorofenil)acetil-4-(S)-benzil-2-oksazolidinona (iz primera 58, korak A) v 40 ml THF. Raztopino acil oksazolidinona mešamo v suhi led/aceton kopeli 10 minut, nato prenesemo preko cevke k raztopini kalijevega bis(trimetilsilil)amida tako hitro, da notranjo temperaturo zmesi ohranimo pod -70 °C. Bučko acil oksazolidinona splaknemo s 15 ml THF in splahovalo dodamo preko cevke k reakcijski zmesi in nastalo zmes mešamo 30 minut pri -78 °C. V peči posušeno, 250 ml bučko z okroglim dnom, opremljeno s prekatom in magnetnim mešalom, splaknemo z dušikom in napolnimo z raztopino 10,89 g (35,0 mmol) 2,4,6triizopropilfenilsulfonil azida v 40 ml THF. Azidno raztopino mešamo v suhi led/aceton kopeli 10 minut, nato preko cevke prenesemo k reakcijski zmesi tako hitro, da notranjo temperaturo zmesi ohranimo pod -70 °C. Po 2 minutah reakcijo pogasimo s 6,0 ml ledocetne kisline, hladilno kopel odstranimo in zmes mešamo 18 ur pri sobni temperaturi. Pogašeno reakcijsko zmes porazdelimo med 300 ml etil acetata in 300 ml 50 %-ne nasičene vodne raztopine natrijevega bikarbonata. Organsko plast ločimo, posušimo preko magnezijevega sulfata in koncentriramo v vakuumu. Flash kromatografija na 500 g silikagela, pri čemer uporabimo 2 : 1 v/v, nato 1 : 1 v/v heksani/metilen klorid kot eluent, zagotovi 5,45 g (67 %) naslovne spojine kot olje.The oven-dried, 11-necked flask equipped with a chamber, a nitrogen inlet, a thermometer and a magnetic stirrer was washed with nitrogen and filled with a solution of 58.0 ml of a 1 M solution of potassium bis (trimethylsilyl) amide in toluene and 85 ml of THF, and cooled to -78 ° C. The oven-dried, 250 ml round-bottom flask fitted with a chamber and a magnetic stirrer was washed with nitrogen and filled with a solution of 7.20 g (23.0 mmol) of 3- (4-fluorophenyl) acetyl-4- (S) - benzyl-2-oxazolidinone (from Example 58, step A) in 40 ml of THF. The acyl oxazolidinone solution was stirred in a dry ice / acetone bath for 10 minutes, then transferred through a tube to a solution of potassium bis (trimethylsilyl) amide so quickly that the internal temperature of the mixture was kept below -70 ° C. Rinse the acyl oxazolidinone flask with 15 ml THF and add the flask via a tube to the reaction mixture and stir the resulting mixture at -78 ° C for 30 minutes. The oven-dried, 250 ml round-bottom flask, equipped with a chamber and a magnetic stirrer, was flushed with nitrogen and filled with a solution of 10.89 g (35.0 mmol) of 2,4,6tisopropylphenylsulfonyl azide in 40 ml of THF. The azide solution was stirred in dry ice / acetone bath for 10 minutes, then transferred through a tube to the reaction mixture so quickly that the internal temperature of the mixture was kept below -70 ° C. After 2 minutes, the reaction was quenched with 6.0 ml glacial acetic acid, the cooling bath was removed and the mixture was stirred for 18 hours at room temperature. The quenched reaction mixture was partitioned between 300 ml of ethyl acetate and 300 ml of 50% saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 500 g of silica gel using 2: 1 v / v then 1: 1 v / v hexanes / methylene chloride as eluent provided 5.45 g (67%) of the title compound as an oil.

IRspekter (čist, cm4): 2104,1781,1702.IR spectrum (pure, cm 4 ): 2104,1781,1702.

Ή-NMR (400 MHz, CDC13) δ 2,86 (dd, 1 H, J = 13,2, 9,6), 3,40 (dd, 1 H, J = 13,2), 4,09 - 4,19 (m, 2 H), 4,62 - 4,68 (m, 1 H), 6,14 (s, 1 H), 7,07 - 7,47 (m, 9 H).Ή-NMR (400 MHz, CDCl 3 ) δ 2.86 (dd, 1 H, J = 13.2, 9.6), 3.40 (dd, 1 H, J = 13.2), 4.09 - 4.19 (m, 2 H), 4.62 - 4.68 (m, 1 H), 6.14 (s, 1 H), 7.07 - 7.47 (m, 9 H).

Analiza za ClgH15FN4O3: izrač. C 61,01 H 4,27 ugot. C 60,99 H 4,19Analysis for C lg H 15 FN 4 O 3 : calc. C 61.01 H 4.27 found. C 60.99 H 4.19

N 15,81 F 5,36N, 15.81; F 5.36

N 15,80 F 5,34N, 15.80; F 5.34

103103

Korak C: (S)-azido-(4-fluorofenil)ocetna kislinaStep C: (S) -Asido- (4-fluorophenyl) acetic acid

Raztopino 5,40 g (15,2 mmol) 3-((S)-azido-(4-fluorofenil))acetil-4-(S)-benzil-2oksazolidinona (iz primera 58, korak B) v 200 ml 3 :1 v/v THF/vode mešamo v ledeni kopeli 10 minut. V enem delu dodamo 1,28 g (30,4 mmol) litijevega hidroksida monohidrata in nastalo zmes hladno mešamo 30 minut.A solution of 5.40 g (15.2 mmol) of 3 - ((S) -azido- (4-fluorophenyl) acetyl-4- (S) -benzyl-2oxazolidinone (from Example 58, step B) in 200 ml 3: 1 v / v THF / water was stirred in an ice bath for 10 minutes. 1.28 g (30.4 mmol) of lithium hydroxide monohydrate were added in one portion and the resulting mixture was stirred cold for 30 minutes.

Reakcijsko zmes porazdelimo med 100 ml metilen klorida in 100 ml 25 %-ne nasičene vodne raztopine natrijevega bikarbonata in plasti ločimo. Vodno plast speremo z 2 x 100 ml metilen klorida in nakisamo do pH 2 z 2 N vodno raztopino klorovodikove kisline. Nastalo zmes ekstrahiramo z 2 x 100 ml etil acetata; ekstrakte združimo, speremo s 50 ml nasičene vodne raztopine natrijevega klorida, posušimo preko magnezijevega sulfata in koncentriramo v vakuumu, da dobimo 2,30 g (77 %) naslovne spojine kot olje, ki jo uporabimo v naslednjem koraku brez nadaljnjega čiščenja.The reaction mixture was partitioned between 100 ml of methylene chloride and 100 ml of 25% saturated aqueous sodium bicarbonate solution and the layers were separated. The aqueous layer was washed with 2 x 100 ml of methylene chloride and acidified to pH 2 with 2 N aqueous hydrochloric acid. The resulting mixture was extracted with 2 x 100 ml ethyl acetate; The extracts were combined, washed with 50 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 2.30 g (77%) of the title compound as an oil, which was used in the next step without further purification.

IR spekter (čist, cm-1): 2111,1724.IR spectrum (pure, cm-1): 2111.1724.

Ή-NMR (400 MHz, CDC13) δ 5,06 (s, 1 H), 7,08 - 7,45 (m, 4 H), 8,75 (širok s, 1 H).Ή-NMR (400 MHz, CDCl 3 ) δ 5.06 (s, 1 H), 7.08 - 7.45 (m, 4 H), 8.75 (broad s, 1 H).

Korak D: (S)-4-(fluorofenil)glicinStep D: (S) -4- (Fluorophenyl) glycine

Zmes 2,30 g (11,8 mmol) (S)-azido-(4-fluorofenil)ocetne kisline (iz primera 58, korak C), 250 mg 10 % paladija na ogljenem katalizatorju in 160 ml 3 : 1 v/v vode/ocetna kislina mešamo 18 ur pod atmosfero dušika. Reakcijsko zmes filtriramo skozi Celite in bučko in filtrno pogačo dobro splaknemo z ~ 1 1 3 : 1 v/v vodo/ocetno kislino. Filtrat koncentriramo v vakuumu do okoli 50 ml volumna. Dodamo 300 ml toluena in zmes koncentriramo, da dobimo trdno snov. Trdno snov suspendiramo v 1 : 1 v/v metanolu/etru, filtriramo in posušimo, da dobimo 1,99 g (100 %) naslovne spojine.A mixture of 2.30 g (11.8 mmol) of (S) -azido- (4-fluorophenyl) acetic acid (from example 58, step C), 250 mg of 10% palladium on carbon catalyst and 160 ml of 3: 1 v / v of water / acetic acid was stirred for 18 hours under a nitrogen atmosphere. The reaction mixture was filtered through Celite and the flask was well rinsed with ~ 1 1 3: 1 in / in water / acetic acid. The filtrate was concentrated in vacuo to about 50 ml volume. 300 ml of toluene was added and the mixture was concentrated to give a solid. The solid was suspended in 1: 1 in / in methanol / ether, filtered and dried to give 1.99 g (100%) of the title compound.

Ή-NMR (400 MHz, D2O + NaOD) δ 3,97 (s, 1 H), 6,77 (jasen t, 2 H, J = 8,8), 7,01 (jasen t, 2 H, J = 5,6).Ή-NMR (400 MHz, D 2 O + NaOD) δ 3.97 (s, 1 H), 6.77 (clear t, 2 H, J = 8.8), 7.01 (clear t, 2 H) , J = 5.6).

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PRIMER 59EXAMPLE 59

3-(S)-(4-fluorofenil)-4-benzil-2-morfolinon3- (S) - (4-Fluorophenyl) -4-benzyl-2-morpholinone

Korak A: N-benzil (S)-(4-fluorofenil)glicinStep A: N-benzyl (S) - (4-fluorophenyl) glycine

Raztopino 1,87 g (11,05 mmol) (S)-(4-fluorofenil)glicina (iz primera 58) inl,12 ml (11,1 mmol) benzaldehida v 11,1 ml 1N vodne raztopine natrijevega hidroksida in 11 ml metanola pri 0 °C obdelamo s 165 mg (4,4 mmol) natrijevega borohidrida. Hladilno kopel odstranimo in nastalo zmes mešamo 30 minut pri sobni temperaturi. K reakcijski zmesi dodamo druge dele benzaldehida (1,12 ml (11,1 mmol)) in natrijevega borohidrida (165 mg, 4,4 mmol) in mešanje nadaljujemo 1,5 ure). Reakcijsko zmes porazdelimo med 100 ml etra in 50 ml vode in plasti ločimo. Vodno plast ločimo in filtriramo, da odstranimo majhno količino netopnega materiala. Filtrat nakisamo do pH 5 z 2 N vodno raztopino klorovodikove kisline in trdno snov, ki se obori, filtriramo, dobro splaknemo z vodo, nato etrom, in jo posušimo, da dobimo 1,95 g naslovne spojine.A solution of 1.87 g (11.05 mmol) of (S) - (4-fluorophenyl) glycine (from Example 58) in 1l, 12 ml (11.1 mmol) of benzaldehyde in 11.1 ml of 1N aqueous sodium hydroxide solution and 11 ml of methanol at 0 ° C was treated with 165 mg (4.4 mmol) of sodium borohydride. The cooling bath was removed and the resulting mixture was stirred for 30 minutes at room temperature. Other parts of benzaldehyde (1.12 ml (11.1 mmol)) and sodium borohydride (165 mg, 4.4 mmol) were added to the reaction mixture and stirring was continued for 1.5 hours). The reaction mixture was partitioned between 100 ml of ether and 50 ml of water and the layers separated. The aqueous layer was separated and filtered to remove a small amount of insoluble material. The filtrate was acidified to pH 5 with a 2 N aqueous hydrochloric acid solution and the precipitated solid was filtered, rinsed well with water, then ether and dried to give 1.95 g of the title compound.

^-NMR (400 MHz, D2O + NaOD) δ 3,33 (AB q, 2 H J = 8,4), 3,85 (s, 1 H), 6,79 7,16 (m, 4 H).1 H-NMR (400 MHz, D 2 O + NaOD) δ 3.33 (AB q, 2 HJ = 8.4), 3.85 (s, 1 H), 6.79 7.16 (m, 4 H) ).

Korak B: 3-(S)-(4-fluorofenil)-4-benzil-2-morfolinonStep B: 3- (S) - (4-Fluorophenyl) -4-benzyl-2-morpholinone

Zmes 1,905 g (7,5 mmol) N-benzil (S)-(4-fluorofenil)glicina, 3,90 ml (22,5 mmol) N,N-diizopropiletilamina, 6,50 ml (75,0 mmol) 1,2-dibromoetana in 40 ml N,Ndimetilformamida mešamo 20 ur pri 100 °C (raztopitev vseh trdnih snovi se pojavi pri segrevanju). Reakcijsko zmes ohladimo in koncentriramo v vakuumu. Ostanek porazdelimo med 250 ml etra in 100 ml 0,5 N raztopine kalijevega hidrogen sulfata in plasti ločimo. Organsko plast speremo s 100 ml nasičene vodne raztopine natrijevega bikarbonata, 3 x 150 ml vode, posušimo preko magnezijevega sulfata, in koncentriramo v vakuumu. Flash kromatografija na 125 g silikagela, pri čemer uporabimo 3 : 1 v/v heksane/eter kot eluent, da 1,58 g (74 %) naslovne spojine kot olje.Mixture of 1.905 g (7.5 mmol) of N-benzyl (S) - (4-fluorophenyl) glycine, 3.90 ml (22.5 mmol) of N, N-diisopropylethylamine, 6.50 ml (75.0 mmol) 1 , 2-dibromoethane and 40 ml of N, N-dimethylformamide are stirred for 20 hours at 100 ° C (dissolution of all solids occurs when heated). The reaction mixture was cooled and concentrated in vacuo. The residue was partitioned between 250 ml of ether and 100 ml of 0.5 N potassium hydrogen sulphate solution and the layers separated. The organic layer was washed with 100 ml of saturated aqueous sodium bicarbonate solution, 3 x 150 ml of water, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography on 125 g of silica gel using 3: 1 v / v hexanes / ether as eluent to give 1.58 g (74%) of the title compound as an oil.

Ή-NMR (400 MHz, CDC13) δ 2,65 (dt, 1 H, J = 3,2, 12,8), 3,00 (dt, 1 H, J = 12,8, 2,8), 3,16 (d, 1 H, J = 13,6), 3,76 (d, 1 H, J = 13,6), 4,24 (s, 1 H), 4,37 (dt, 1 H, J = 13,2, 3,2), 4,54 (dt, 1 H, J = 2,8,13,2), 7,07 - 7,56 (m, 9 H).Ή-NMR (400 MHz, CDCl 3 ) δ 2.65 (dt, 1 H, J = 3.2, 12.8), 3.00 (dt, 1 H, J = 12.8, 2.8) , 3.16 (d, 1 H, J = 13.6), 3.76 (d, 1 H, J = 13.6), 4.24 (s, 1 H), 4.37 (dt, 1 H, J = 13.2, 3.2), 4.54 (dt, 1 H, J = 2.8, 13.2), 7.07 - 7.56 (m, 9 H).

105105

PRIMER 60EXAMPLE 60

2-(S)-(3.5-bis(trifluorometil)benziloksil-3-(S)-(4-fluorofenil)-4-benzilmorfolin2- (S) - (3,5-bis (trifluoromethyl) benzyloxyl-3- (S) - (4-fluorophenyl) -4-benzylmorpholine

Naslovno spojino pripravimo v 72 %-nem dobitku iz 3-(S)-(4-fluorofenil)-4-benzil-2morfolinona (iz primera 59), pri čemer uporabimo postopke analogne tistim v primeru 15, koraka A in B.The title compound was prepared in 72% yield from 3- (S) - (4-fluorophenyl) -4-benzyl-2morpholinone (Example 59), using procedures analogous to those in Example 15, steps A and B.

Ή-NMR (200 MHz, CDC13) δ 2,37 (dt, 1 H, J = 3,6,11,8), 2,83 - 2,90 (m, 2 H), 3,55 3,63 (m, 2 H), 3,85 (d, 1 H, J = 13,4), 4,14 (dt, 1 H, J = 2,0,11,8), 4,44 (d, 1 H, J = 13,6), 4,66 (d, 1 H, J = 2,8), 4,79 (d, 1 H, J = 13,4), 7,00 - 7,70 (12 H).Ή-NMR (200 MHz, CDCl 3 ) δ 2.37 (dt, 1 H, J = 3.6, 11.8), 2.83 - 2.90 (m, 2 H), 3.55 3, 63 (m, 2 H), 3.85 (d, 1 H, J = 13.4), 4.14 (dt, 1 H, J = 2.0.11.8), 4.44 (d, 1 H, J = 13.6), 4.66 (d, 1 H, J = 2.8), 4.79 (d, 1 H, J = 13.4), 7.00 - 7.70 ( 12 H).

PRIMER 61EXAMPLE 61

2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-(4-fluorofenil)morfolin2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) - (4-fluorophenyl) morpholine

Naslovno spojino pripravimo v 70 %-nem dobitku iz 2-(S)-(3,5bis(trifluorometil)benziloksi)-3-(S)-(4-fluorofenil)-4-benzilmorfolina (iz primera 60), pri čemer uporabimo postopek analogen tistemu v primeru 15, korak C.The title compound was prepared in 70% yield from 2- (S) - (3,5bis (trifluoromethyl) benzyloxy) -3- (S) - (4-fluorophenyl) -4-benzylmorpholine (Example 60), using a process analogous to that in Example 15, step C.

Masni spekter (FAB): m/Z 424 (M+H, 40 %).Mass spectrum (FAB): m / Z 424 (M + H, 40%).

Ή-NMR (400 MHz, CDC13) δ 1,80 (širok s, 1 H), 3,11 (jasen dd, 1 H, J = 2,2,12,4), 3,25 (dt, 1 H, J = 3,6,12,4), 3,65 (jasen dd, 1 H, J = 3,6,11,4), 4,05 (dt, 1 H, J = 2,2, 11,8), 4,11 (d, 1 H, J = 2,2), 4,53 (d, 1 H, J = 13,6), 4,71 (d, 1 H, J = 2,2), 4,83 (d, 1 H, J = 13,6), 7,04 (t, 2 H, J = 7,2), 7,33 - 7,37 (m, 2 H), 7,42 (s, 2 H), 7,72 (s, 1 H).Ή-NMR (400 MHz, CDCl 3 ) δ 1.80 (broad s, 1 H), 3.11 (clear dd, 1 H, J = 2.2, 12.4), 3.25 (dt, 1 H, J = 3,6,12,4), 3,65 (clear dd, 1 H, J = 3,6,11,4), 4,05 (dt, 1 H, J = 2,2, 11 , 8), 4.11 (d, 1 H, J = 2.2), 4.53 (d, 1 H, J = 13.6), 4.71 (d, 1 H, J = 2.2) ), 4.83 (d, 1 H, J = 13.6), 7.04 (t, 2 H, J = 7.2), 7.33 - 7.37 (m, 2 H), 7. 42 (s, 2H), 7.72 (s, 1H).

PRIMER 62EXAMPLE 62

2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-(4-fluorofenil)-4-(3-(5-okso-lH,4H-l,2,4-triazolo)metilmorfolin2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) - (4-fluorophenyl) -4- (3- (5-oxo-1H, 4H-1,2,4- triazolo) methylmorpholine

Naslovno spojino pripravimo v 69 %-nem dobitku iz 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(S)-(4-flurofenil)morfolina (iz primera 61), pri čemer uporabimo postopek analogen tistemu v primeru 18.The title compound was prepared in 69% yield from 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (S) - (4-fluorophenyl) morpholine (Example 61) using the procedure analogous to that in Example 18.

106106

Masni spekter (FAB): m/Z 521 (M+H, 100 %).Mass spectrum (FAB): m / Z 521 (M + H, 100%).

4H-NMR (400 MHz, CDC13) δ 2,55 (dt, 1 H, J = 3,6, 12,0), 2,91 (d, 1 H, J = 11,6), 2,93 (d, 1 H, J = 14,4), 3,57 (d, 1 H, J = 2,8), 3,59 (d, 1 H, J = 14,4), 3,67 - 3,70 (m, 1 H), 4,18 (dt, 1 H, J = 2,4,11,6), 4,48 (d, 1 H, J = 13,6), 4,65 (d, 1 H, J = 2,8), 4,84 (d, 1 H, J = 13,6), 7,07 (t, 2 H, J = 8,4), 7,40 (s, 2 H), 7,45 - 7,48 (m, 2 H), 7,68 (s, 1 H), 10,04 (širok s, 1 H), 10,69 (širok s, 1 H). 4 H-NMR (400 MHz, CDCl 3 ) δ 2.55 (dt, 1 H, J = 3.6, 12.0), 2.91 (d, 1 H, J = 11.6), 2. 93 (d, 1 H, J = 14.4), 3.57 (d, 1 H, J = 2.8), 3.59 (d, 1 H, J = 14.4), 3.67 - 3.70 (m, 1H), 4.18 (dt, 1H, J = 2.4, 11.6), 4.48 (d, 1H, J = 13.6), 4.65 ( d, 1 H, J = 2.8), 4.84 (d, 1 H, J = 13.6), 7.07 (t, 2 H, J = 8.4), 7.40 (s, 2 H), 7.45 - 7.48 (m, 2 H), 7.68 (s, 1 H), 10.04 (broad s, 1 H), 10.69 (broad s, 1 H).

Analiza za C22H19F?N4O3:Analysis for C 22 H 19 F ? N 4 O 3 :

izrač. C 50,78 H 3,68 N 10,77 F 25,55 ugot. C 50,89 H 3,76 N 10,62 F 25,56calcd. C 50.78 H 3.68 N 10.77 F 25.55 found. C 50.89 H 3.76 N 10.62 F 25.56

PRIMER 63EXAMPLE 63

2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-((3-piridil)metilkarbonil)-3-(R)-fenilmorfolin2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4 - ((3-pyridyl) methylcarbonyl) -3- (R) -phenylmorpholine

Raztopino 55 mg (0,315 mmol) 4-piridilocetne kisline v 1 ml CH2C12, ki vsebuje 0,079 ml (0,715 mmol) N-metilmorfolina, 53 mg (0,37 mmol) HOBt in 73 mg (0,37 mmol) EDC mešamo 10 min. Dodamo raztopino 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3(R)-fenilmorfolina (iz primera 33) v 1 ml CH2C12. Po mešanju zmesi 2 h, jo porazdelimo med vodo in CH2C12. Organsko plast speremo z vodo, slanico in jo posušimo s filtriranjem preko Na2SO4. Filtrat koncentriramo in ostanek prečistimo s flash kromatografijo, pri čemer uporabimo 70 % EtOAc/heksan, da dobimo 152 mg (100 % dobitek) produkta.A solution of 55 mg (0.315 mmol) of 4-pyridylacetic acid in 1 ml of CH 2 C1 2 containing 0.079 ml (0.715 mmol) of N-methylmorpholine, 53 mg (0.37 mmol) of HOBt and 73 mg (0.37 mmol) of EDC stirred for 10 min. A solution of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3 (R) -phenylmorpholine (Example 33) was added in 1 ml of CH 2 Cl 2 . After stirring the mixture for 2 h, it was partitioned between water and CH 2 Cl 2 . The organic layer was washed with water, brine and dried by filtration over Na 2 SO 4 . The filtrate was concentrated and the residue purified by flash chromatography using 70% EtOAc / hexane to give 152 mg (100% yield) of the product.

XH-NMR (400 MHz, CDC13) δ 3,0 - 3,85 (m, 5 H), 3,95 & 4,4 (širok s, 1 H), 4,66 (d, J = 13 Hz, 1 H), 4,82 (d, J = 13 Hz, 1 H), 5,0 & 5,9 (širok s, 1 H), 5,23 (s, 1 H), 7,1 7,65 (m, 7 H), 7,8 (m, 3 H), 8,43 (širok s, 2 H). X H-NMR (400 MHz, CDCl 3 ) δ 3.0 - 3.85 (m, 5 H), 3.95 & 4.4 (broad s, 1 H), 4.66 (d, J = 13 Hz, 1 H), 4.82 (d, J = 13 Hz, 1 H), 5.0 & 5.9 (broad s, 1 H), 5.23 (s, 1 H), 7.1 7 , 65 (m, 7 H), 7.8 (m, 3 H), 8.43 (broad s, 2 H).

PRIMER 64EXAMPLE 64

2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-(metoksikarbonilpentil)-3-(R)fenilmorfolin2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (methoxycarbonylpentyl) -3- (R) phenylmorpholine

K raztopini 0,259 g (0,64 mmol) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-3-(R)107 fenilmorfolina (iz primera 33) v 2 ml DMF dodamo 0,16 g (0,77 mmol) metil 6-bromoheksanoata, 0,155 g (1,12 mmol) K^COj in 2 kristala nBu4NI. Nastalo raztopino segrevamo 36 h v 60 °C kopeli, v tem času tankoplastna tekočinska kromatografija kaže na nedokončano reakcijo. Temperaturo kopeli povišano do 100 °C. Po 3 h reakcijsko zmes ohladimo in razredčimo z EtOAc. EtOAc raztopino speremo z vodo (2 x), slanico in jo posušimo preko Na2SO4. Filtrat koncentriramo in ostanek kromatografiramo z uporabo 30 % EtOAc/heksana, da izoliramo 220 mg (65 %) produkta.To a solution of 0.259 g (0.64 mmol) of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -3- (R) 107 phenylmorpholine (from Example 33) in 0.1 ml of DMF was added 0.16 g ( 0.77 mmol) of methyl 6-bromohexanoate, 0.155 g (1.12 mmol) of K 2 CO 2 and 2 crystals of nBu 4 NI. The resulting solution was heated for 36 h in a 60 ° C bath, during which time thin-layer liquid chromatography indicated an incomplete reaction. Bath temperature increased to 100 ° C. After 3 h, the reaction mixture was cooled and diluted with EtOAc. The EtOAc solution was washed with water (2 x), brine and dried over Na 2 SO 4 . The filtrate was concentrated and the residue chromatographed using 30% EtOAc / hexane to isolate 220 mg (65%) of the product.

^-NMR (400 MHz, CDC13) δ 1,0 -1,4 (m, 4 H), 1,47 (m, J = 8 Hz, 2 H), 1,95 (m, 1 H), 2,2 (t, J = 8 Hz, 2 H), 2,35 (m, 2 H), 2,9 (d, J = 13 Hz, 1 H), 3,07 (d, J = 7 Hz, 1 H), 3,62 (s, 3 H), 3,81 (td, J = 8 Hz in 2 Hz, 1 H), 4,04 (dd, J = 10 Hz in 2 Hz, 1 H), 4,36 (d, J = 7 Hz, 1 H), 4,4 (d, J = 13 Hz, 1 H) 4,79 (d, J = 13 Hz, 1 H), 7,2 - 7,4 (m, 7 H), 7,66 (s, 1 H).1 H-NMR (400 MHz, CDCl 3 ) δ 1.0 -1.4 (m, 4 H), 1.47 (m, J = 8 Hz, 2 H), 1.95 (m, 1 H), 2.2 (t, J = 8 Hz, 2 H), 2.35 (m, 2 H), 2.9 (d, J = 13 Hz, 1 H), 3.07 (d, J = 7 Hz) , 1 H), 3.62 (s, 3 H), 3.81 (td, J = 8 Hz and 2 Hz, 1 H), 4.04 (dd, J = 10 Hz and 2 Hz, 1 H) , 4.36 (d, J = 7 Hz, 1 H), 4.4 (d, J = 13 Hz, 1 H) 4.79 (d, J = 13 Hz, 1 H), 7.2 - 7 , 4 (m, 7H), 7.66 (s, 1H).

PRIMER 65EXAMPLE 65

2-(S)-(3,5-bis(trifluorometil)benziloksi)-4-(karboksipentil)-3-(R)-fenilmorfolin2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4- (carboxypentyl) -3- (R) -phenylmorpholine

Raztopino 0,15 g (0,28 mmol) 2-(S)-(3,5-bis(trifluorometil)benziloksi)-4(metoksikarbonilpentil)-3-(R)-fenilmorfolina (iz primera 64) v 3 ml MeOH umilimo z obdelovanjem 40 min. pri 65 °C z 0,5 ml 5 N NaOH. Raztopino ohladimo, koncentriramo in ostanek razredčimo z vodo. Vodno raztopino naravnamo na pH 6 z dodajanjem 2 N HC1 in jo ekstrahiramo z EtOAc. Organsko plast speremo s slanico, posušimo in koncentriramo. Ostanek po kromatografiji na flash koloni s 50 % EtOAc/heksanom zagotovi 0,13 g (89 %) produkta.A solution of 0.15 g (0.28 mmol) of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy) -4 (methoxycarbonylpentyl) -3- (R) -phenylmorpholine (Example 64) in 3 ml of MeOH soap by treatment for 40 min. at 65 ° C with 0.5 ml of 5 N NaOH. The solution was cooled, concentrated and the residue was diluted with water. The aqueous solution was adjusted to pH 6 by the addition of 2 N HCl and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated. Flash column chromatography with 50% EtOAc / hexane provided 0.13 g (89%) of the product.

'H-NMR (400 MHz, CDC13) δ 1,0 -1,5 (m, 4 H), 1,5 (m, 2 H), 2,2 (m, 2 H), 2,35 (m, 2 H), 2,9 (d, J = 13 Hz, 1 H), 3,08 (d, J = 7 Hz, 1 H), 3,82 (t, J = 8 Hz, 1 H), 4,09 (d, J = 7 Hz, 1 H) 4,38 (s, 1 H), 4,4 (d, J = 13 Hz, 1 H), 4,79 (d, J = 13 Hz, 1 H), 7,2 - 7,4 (m, 7 H), 7,66 (s, 1 H).1 H-NMR (400 MHz, CDCl 3 ) δ 1.0 -1.5 (m, 4 H), 1.5 (m, 2 H), 2.2 (m, 2 H), 2.35 ( m, 2 H), 2.9 (d, J = 13 Hz, 1 H), 3.08 (d, J = 7 Hz, 1 H), 3.82 (t, J = 8 Hz, 1 H) , 4.09 (d, J = 7 Hz, 1 H) 4.38 (s, 1 H), 4.4 (d, J = 13 Hz, 1 H), 4.79 (d, J = 13 Hz) , 1 H), 7.2 - 7.4 (m, 7 H), 7.66 (s, 1 H).

108108

PRIMER 66EXAMPLE 66

2- (S)-(3,5-bis(trifluorometil)benziloksi-4-(metilaminokarbonilpentil)-6-okso-heksil)~2- (S) - (3,5-bis (trifluoromethyl) benzyloxy-4- (methylaminocarbonylpentyl) -6-oxo-hexyl) -

3- (R)-fenilmorfoIin3- (R) -phenylmorpholine

Raztopino 116 mg (0,22 mmol) 2-(S)-(3,5-bis(trifluorometil)benziloksi-4(karboksipentil)-3-(R)-fenilmorfolina (iz primera 65) v 1 ml CH2C12 obdelamo s 40 mg (0,29 mmol) HOBt, 57 mg (0,29 mmol) EDC in 0,037 ml N-metilmorfolina. Po 10 min. dodamo 0,027 ml (0,3 mmol) vodnega metilamina (40 %) in nastalo zmes mešamo 4 h. Reakcijsko zmes razredčimo z vodo in ekstrahiramo s CH2C12. Združeno CH2C12 plast speremo z vodo, slanico in jo posušimo preko Na2SO4, in filtrat koncentriramo. Prečiščenje ostanka na flash koloni z EtOAc zagotovi 0,10 g produkta.A solution of 116 mg (0.22 mmol) of 2- (S) - (3,5-bis (trifluoromethyl) benzyloxy-4 (carboxypentyl) -3- (R) -phenylmorpholine (Example 65) in 1 ml of CH 2 C1 2 was treated with 40 mg (0.29 mmol) of HOBt, 57 mg (0.29 mmol) of EDC and 0.037 ml of N-methylmorpholine, followed by 0.027 ml (0.3 mmol) of aqueous methylamine (40%) after 10 min and the resulting mixture The reaction mixture was diluted with water and extracted with CH 2 Cl 2 The combined CH 2 Cl 2 layer was washed with water, brine and dried over Na 2 SO 4 , and the filtrate was concentrated Purification of the residue on a flash column with EtOAc provided 0 , 10 g of product.

Ή-NMR (400 MHz, CDC13) δ 1,0 -1,4 (m, 4 H), 1,47 (m, 2 H), 1,95 (m, 1 H), 2,04 (t, J = 8 Hz, 2 H), 2,35 (m, 2 H), 2,74 (d, J = 5 Hz, 3 H), 2,89 (d, J = 12 Hz, 1 H) 3,08 (d, J = 7 Hz, 1 H), 3,81 (t, J = 7 Hz, 1 H), 4,02 (d, J = 11 Hz, 1 H), 4,36 (d, J = 7 Hz, 1 H), 4,39 (d, J = 13 Hz, 1 H), 4,79 (d, J = 13 Hz, 1 H), 5,03 (širok s, 1 H), 7,2 - 7,4 (m, 7 H), 7,65 (s, 1 H).Ή-NMR (400 MHz, CDCl 3 ) δ 1.0 -1.4 (m, 4 H), 1.47 (m, 2 H), 1.95 (m, 1 H), 2.04 (t , J = 8 Hz, 2 H), 2.35 (m, 2 H), 2.74 (d, J = 5 Hz, 3 H), 2.89 (d, J = 12 Hz, 1 H) 3 , 08 (d, J = 7 Hz, 1 H), 3.81 (t, J = 7 Hz, 1 H), 4.02 (d, J = 11 Hz, 1 H), 4.36 (d. J = 7 Hz, 1 H), 4.39 (d, J = 13 Hz, 1 H), 4.79 (d, J = 13 Hz, 1 H), 5.03 (broad s, 1 H). 7.2 - 7.4 (m, 7H), 7.65 (s, 1H).

PRIMER 67EXAMPLE 67

Značilni farmacevtski sestavki, ki vsebujejo spojino v smislu izumaTypical pharmaceutical compositions comprising a compound of the invention

A: Suho polnjene kapsule, ki vsebujejo 50 mg aktivne sestavine na kapsuloA: Dry capsules containing 50 mg of active ingredient per capsule

Sestavina aktivna sestavina laktoza magnezijev stearat kapsula (velikost št. 1)Active ingredient lactose magnesium stearate capsule (size # 1)

Količina na kapsulo (mg)Amount per capsule (mg)

149149

200200

109109

Aktivno sestavino lahko zmanjšamo do št. 60 praška in laktozo in magnezijev stearat lahko spustimo preko št. 60 pivnate podlage na prašek. Združene sestavine lahko nato mešamo okoli 10 minut in napolnimo v št. 1 suho želatinsko kapsulo.The active ingredient can be reduced to no. 60 powder and lactose and magnesium stearate can be dropped via no. 60 beer bases per powder. The combined ingredients can then be stirred for about 10 minutes and filled into no. 1 dry gelatin capsule.

B: TabletaB: Tablet

Značilna tableta bo vsebovala aktivno sestavino (25 mg), preželatiniran škrob USP (82 mg), mikrokristalinično celulozo (82 mg) in magnezijev stearat (1 mg).The typical tablet will contain the active ingredient (25 mg), pregelatinized USP starch (82 mg), microcrystalline cellulose (82 mg) and magnesium stearate (1 mg).

C: SvečkaC: Candle

Značilni supozitorni pripravki za rektalno dajanje vsebujejo aktivno sestavino (0,08 1,0 mg), dinatrijev kalcijev edetat (0,25 - 0,5 mg) in polietilen glikol (775 - 1600 mg). Ostale supozitorne pripravke lahko naredimo z npr. substitucijo dinatrijevega kalcijevega edetata z butiliranim hidroksi toluenom (0,04 - 0,08 mg) in s substitucijo polietilen glikola s hidrogeniranim raslinskim oljem (675 - 1400 mg) kot je Suppocire L, Wecobee FS, Wecobee M, Witepsols, in podobni.Typical rectal administration suppository preparations contain the active ingredient (0.08 1.0 mg), disodium calcium edetate (0.25 - 0.5 mg) and polyethylene glycol (775 - 1600 mg). Other suppository preparations can be made by e.g. disodium calcium edetate substitution with butylated hydroxy toluene (0.04-0.08 mg) and substitution of polyethylene glycol with hydrogenated vegetable oil (675-1400 mg) such as Suppocire L, Wecobee FS, Wecobee M, Witepsols, and the like.

D: InjekcijaD: Injection

Značilni injekcijski pripravki vsebujejo aktivno sestavino natrijev fosfat dibazičen anhidrid (11,4 mg), benzil alkohol (0,01 ml) in vodo za injekcijo (1,0 ml).Typical injectable preparations contain the active ingredient sodium phosphate dibasic anhydride (11.4 mg), benzyl alcohol (0.01 ml) and water for injection (1.0 ml).

Medtem ko predhodne specifikacije navajajo principe v smislu predloženega izuma, s primeri, podanimi za ilustrativni namen, je razumeti, da praksa predloženega izuma vključuje vse običajne variacije, prilagoditve, modifikacije, brisanja ali dodajanja postopkov in protokolov opisanih tu notri, kot pridejo znotraj obsega naslednjih zahtevkov in njihovih ekvivalentov.While the foregoing specifications state the principles of the present invention, with the examples given for illustrative purpose, it is to be understood that the practice of the present invention includes all the usual variations, adjustments, modifications, deletions or additions of the processes and protocols described herein as coming within the scope of the following claims and their equivalents.

ZaFor

MERCK &CO., INC.:MERCK & CO., INC .:

patentna pisarnapatent office

UJUBLJANAUJUBLJANA

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Claims (2)

1. Spojina s strukturno formulo:A compound having the structural formula: ali njena farmacevtsko sprejemljiva sol, označena s tem, daje:or a pharmaceutically acceptable salt thereof, characterized in that: R1 izbran iz skupine, ki sestoji iz:R 1 selected from the group consisting of: (1) vodika;(1) hydrogen; (2) alkila, nesubstituiranega ali substituiranega z enim ali večimi izmed substituentov, izbranih iz:(2) alkyl, unsubstituted or substituted by one or more of the substituents selected from: (a) hidroksi, (b) okso, (c) C145 alkoksi, (d) fenil-Cj 3 alkoksi, (e) fenila, (f) -CN, (g) halo, (h) -NR2 * * * * * * 9R1(), kjer sta R9 in R10 neodvisno izbrana iz:(a) hydroxy, (b) oxo, (c) C 145 alkoxy, (d) phenyl-C 3 alkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR 2 * * * * * 9 R 1 () , where R 9 and R 10 are independently selected from: (i) vodika, (ii) Cw alkila, (iii) hidroksi-C^ alkila in (iv) fenila, (i) -NR9COR10, kjer sta R9 in R10 kot je definirano zgoraj, (j) -NR9CO2R10, kjer sta R9 in R10 kot je definirano zgoraj, (k) -CONR9R10, kjer sta R9 in R10 kot je definirano zgoraj, (l) -COR9, kjer je R9, kot je definirano zgoraj, (m) -CO2R9, kjer je R9, kot je definirano zgoraj;(i) hydrogen, (ii) C w alkyl, (iii) hydroxy-C 1-6 alkyl, and (iv) phenyl, (i) -NR 9 COR 10 , wherein R 9 and R 10 are as defined above, (j) -NR 9 CO 2 R 10 where R 9 and R 10 are as defined above, (k) -CONR 9 R 10 where R 9 and R 10 are as defined above, (l) -COR 9 where R 9 as defined above, (m) -CO 2 R 9 , wherein R 9 is as defined above; (n) heterocikla, kjer je heterocikel izbran iz skupine, ki sestoji iz:(n) heterocycle, wherein the heterocycle is selected from the group consisting of: 111111 (A) (A) benzimidazolila, benzimidazolyl, (B) (B) benzofuranila, benzofuranyl, (C) (C) benzotiofenila, benzothiophenyl, (D) (D) benzoksazolila, benzoxazolyl, (E) (E) furanila, furanila, (F) (F) imidazolila, imidazolyl, (G) (G) indolila, indolila, (H) (H) izooksazolila, isooxazolyl, (I) (I) izotiazolila, isothiazolyl, (J) (J) oksadiazolila, oxadiazolyl, (K) (K) oksazolila, oxazolyl, (L) (L) pirazinila, pyrazinyl, (M) (M) pirazolila, pyrazolyl, (N) (N) piridila, pyridyl, (0) (0) pirimidila, pyrimidyl, (P) (P) pirolila, pyrolyl, (Q) (Q) kinolila, quinolyl, (R) (R) tetrazolila, tetrazolyl, (S) (S) tiadiazolila, tiadiazolila, (O (Oh tiazolila, thiazolyl, (U) (U) tienila, tienila, (V) (V) triazolila, triazolyl, (W) (W) azetidinila, azetidinyl, (X) (X) 1,4-dioksanila, 1,4-dioxanyl, (Y) (Y) heksahidroazepinila, hexahydroazepinyl, (Z) (Z) oksanila, oxanyl, (AA) (AA) piperazinila, piperazinil, (AB) (AB) piperidinila, piperidinyl, (AC) (AC) pirolidinila, pyrrolidinyl, (AD) (AD) tetrahidrofuranila in tetrahydrofuranyl and (AE) (AE) tetrahidrotienila, tetrahydrothienyl, in kjer je heterocikel nesubstituiran ali substituiran z enim ali večimi substituenti, izbranimi iz: and wherein the heterocycle is unsubstituted or substituted by one or more substituents selected from: (i) (i) alkila, nesubstituiranega ali substituiranega s halo, -CF3, -OCH3 ali fenilom,alkyl unsubstituted or substituted by halo, -CF 3 , -OCH 3 or phenyl, (h) (h) Cj 6 alkoksi, C1-6 alkoxy, (iii) (iii) okso, okso, (iv) (iv) hidroksi, hydroxy,
112 (v) tiokso, (vi) -SR9, kjer je R9 kot je definirano zgoraj, (vii) halo, (viii) ciano, (ix) fenila, (x) trifluorometila,112 (v) thioxo, (vi) -SR 9 , where R 9 is as defined above, (vii) halo, (viii) cyano, (ix) phenyl, (x) trifluoromethyl,
SI9300346A 1992-06-29 1993-06-29 Morpholine and thiomorpholine tachyquinine-receptor antagonists SI9300346B (en)

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